Methods for the safe administration of imidazole or imidazolium compounds

ABSTRACT

Methods for the safe administration of imidazole or imidazolium compounds, and conditions that may be treated by these methods, are described herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 14/625,457, filed Feb. 18, 2015, which is acontinuation-in-part of U.S. patent application Ser. No. 14/446,184,filed Jul. 29, 2014, now U.S. Pat. No. 9,006,279; U.S. patentapplication Ser. No. 14/625,457 is also a continuation-in-part of U.S.patent application Ser. No. 14/536,526, filed Nov. 7, 2014, nowabandoned, which is a continuation-in-part of U.S. patent applicationSer. No. 14/446,184, which is a divisional of U.S. patent applicationSer. No. 14/288,716, filed May 28, 2014, now U.S. Pat. No. 8,835,650,which claims benefit of U.S. Prov. App. No. 61/933,608, filed Jan. 30,2014; the above U.S. patent application Ser. No. 14/536,526 is also acontinuation-in-part of U.S. patent application Ser. No. 14/279,229,filed May 15, 2014, now U.S. Pat. No. 9,034,889, which is a continuationof U.S. patent application Ser. No. 14/063,979, filed Oct. 25, 2013, nowU.S. Pat. No. 8,802,658, which is a continuation-in-part of U.S. patentapplication Ser. No. 13/894,274, filed May 14, 2013, which claims thebenefit of U.S. Prov. App. No. 61/646,538, filed May 14, 2012;61/647,478, filed May 15, 2012; 61/654,292, filed Jun. 1, 2012;61/654,383, filed Jun. 1, 2012; 61/655,527, filed Jun. 5, 2012;61/655,541, filed Jun. 5, 2012; 61/764,563, filed Feb. 14, 2013;61/762,225, filed Feb. 7, 2013; 61/767,647, filed Feb. 21, 2013;61/767,676, filed Feb. 21, 2013; and 61/803,721, filed Mar. 20, 2013.

SUMMARY

Bisphosphonate compounds are potent inhibitors of osteoclast activity,and are used clinically to treat bone-related conditions such asosteoporosis and Paget's disease of bone; and cancer-related conditionsincluding multiple myeloma, and bone metastases from solid tumors. Theygenerally have low oral bioavailability.

Patchy osteoporosis and bone marrow edema may result from osteoclasthyperactivity. Zoledronic acid is a potent inhibitor of bone resorptionand osteoclast activity. Nitrogen containing bisphosphonates, such aszoledronic acid, also inhibit the mevalonate pathway in the osteoclastthereby interrupting normal osteoclast function.

It has been discovered that oral dosage forms of bisphosphonatecompounds, such as zoledronic acid, can be used to treat or alleviatepain or related conditions.

Some embodiments include a method of enhancing the oral bioavailabilityof zoledronic acid comprising orally administering a dosage formcontaining zoledronic acid in the disodium salt form.

Some embodiments include a dosage form comprising zoledronic acid in thedisodium salt form, wherein the bioavailability, in a mammal, ofzoledronic acid in the disodium salt form is greater than thebioavailability of zoledronic acid in the diacid form would be in thesame dosage form.

Some embodiments include a dosage form comprising zoledronic acid,wherein the dosage form contains an amount of zoledronic acid in thedisodium salt form that provides an area under the plasma concentrationcurve of zoledronic acid of about 4 ng·h/mL to about 2000 ng·h/mL to ahuman being to which the dosage form is administered.

Some embodiments include a dosage form comprising zoledronic acid in thedisodium salt form, wherein the disodium salt form is present in a lowermolar amount than would be present if the zoledronic acid were in thediacid form; and wherein the zoledronic acid in the disodium salt formhas an improved bioavailability as compared to the zoledronic acid inthe diacid form to the extent that the lower molar amount of thedisodium salt in the dosage form does not reduce the amount ofzoledronic acid delivered to the plasma of a mammal.

Although an oral dosage form with enhanced bioavailability with respectto the bisphosphonate compound can be used, the treatment can also beeffective using an oral dosage form that includes a bisphosphonatecompound, such as zoledronic acid, wherein the bioavailability of thebisphosphonate is unenhanced, or is substantially unenhanced.

Some embodiments include a method of relieving inflammatory paincomprising administering an oral dosage form containing zoledronic acidto a mammal in need thereof, wherein the mammal experiences significantpain relief more than 3 hours after administration of the dosage form.

Some embodiments include a method of relieving pain associated with anarthritis comprising administering an oral dosage form containingzoledronic acid to a human being in need thereof.

Some embodiments include a method of treating complex regional painsyndrome comprising administering an oral dosage form containingzoledronic acid to a mammal in need thereof.

Some embodiments include an oral dosage form comprising zoledronic acid,wherein the oral bioavailability of zoledronic acid is substantiallyunenhanced. For example, in some embodiments, the oral bioavailabilityin the dosage form is about 0.01% to about 4%.

Some embodiments include a pharmaceutical product comprising more thanone unit of an oral dosage form described herein. In some embodiments,each unit of the oral dosage form contains about 1 mg to about 50 mg ofzoledronic acid.

Some embodiments include a method of relieving inflammatory paincomprising administering an oral dosage form containing zoledronic acidto a mammal in need thereof.

In some embodiments, the mammal receives a total monthly dose ofzoledronic acid that is about 800 mg/m² or less.

In some embodiments, the dosage form contains about 10 mg/m² to about 20mg/m² based upon the body surface area of the mammal.

Some embodiments include a method of relieving inflammatory paincomprising orally administering zoledronic acid to a mammal in needthereof.

In some embodiments, about 300 mg/m² to about 600 mg/m² of zoledronicacid is administered per month, based upon the body surface area of themammal.

In some embodiments, about 50 mg/m² to about 600 mg/m² of zoledronicacid is administered per month, based upon the body surface area of themammal.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a plot of pain compression thresholds in a rat model ofinflammatory pain using three different doses of zoledronic acid.Measurements were taken at baseline (BL) and at various time pointsafter dosing on the days indicated.

FIG. 2A is a graph depicting reversal of arthritis pain for twodifferent doses of zoledronic acid in a rat model of arthritis pain.

FIG. 2B is a graph depicting pain thresholds for two different doses ofzoledronic acid in a rat model of arthritis pain.

FIG. 3 is a graph summarizing the results for vehicle and zoledronicacid treated rats in a rat model of complex regional pain syndrome.

FIG. 4 depicts hindpaw pain thresholds for vehicle and zoledronic acidtreated rats in a rat model of complex regional pain syndrome.

FIG. 5 depicts weight bearing for vehicle and zoledronic acid treatedrats in a rat model of complex regional pain syndrome.

FIG. 6 depicts paw thickness change for vehicle and zoledronic acidtreated rats in a rat model of complex regional pain syndrome.

FIG. 7 depicts the aqueous solubility of disodium zoledronatetetrahydrate as compared to the diacid form of zoledronic acid.

FIG. 8 depicts the plasma concentration of zoledronic acid in dogs overtime after administration of 150 mg of the disodium salt form ofzoledronic acid and the diacid form of zoledronic acid.

FIG. 9 depicts the compressibility of dosage forms containing zoledronicacid in the disodium salt form as compared to the diacid form.

FIG. 10 depicts the change in VAS pain score compared to placebo atthree months with zoledronic acid treatment in patients withosteoarthritis of the knee, bone marrow lesions, and different degreesof joint space narrowing.

FIG. 11 depicts the change in VAS pain score compared to baseline atthree months with zoledronic acid treatment in patients withosteoarthritis of the knee, bone marrow lesions, and different degreesof joint space narrowing.

FIG. 12 depicts the change in VAS pain score compared to placebo atthree months with zoledronic acid treatment in different subgroups ofpatients with osteoarthritis of the knee and bone marrow lesions.

FIG. 13 depicts the change in BML lesion size compared to placebo at sixmonths with zoledronic acid treatment in patients with osteoarthritis ofthe knee, bone marrow lesions, and different degrees of joint spacenarrowing.

DETAILED DESCRIPTION

Inhibitors of osteoclast activity include bisphosphonate compounds suchas pamidronate or pamidronic acid, neridronate or neridronic acid,olpadronate or olpadronic acid, alendronate or alendronic acid,incadronate or incadronic acid, ibandronate or ibandronic acid,risedronate or risedronic acid, cimadronate or cimadronic acid,zoledronate or zoledronic acid, etidronate or etidronic acid, clodronateor clodronic acid, tiludronate or tiludronic acid, etc.

RANK/RANKL antagonists may be inhibitors of osteoclast activity.RANK/RANKL antagonists include but are not limited to OPG(osteoprotegerin) or a variant thereof, an anti-RANKL antibody such asdenosumab, a monoclonal anti-RANKL antibody, a small interfering RNA, amicroRNA, a precursor molecule, a ribozyme, an antisense nucleic acid,or an aptamer targeting RANKL. Antibodies such as AB-25E9, smallmolecules, small interfering RNAs, microRNAs, precursor molecules,ribozymes, antisense nucleic acids, or aptamers that target thecell-surface protein Siglec-15 may be osteoclast inhibitors.

Some Bruton's tyrosine kinase (BTK) inhibitors may be inhibitors ofosteoclast activity. BTK inhibitors can include ONO-4059; ibrutinib;Benzo[b]thiophene-2-carboxamide, N-[3-[6-[[4-[(2R)-1,4-dimethyl-3-oxo-2-piperazinyl]phenyl]amino]-4,5-dihydro-4-methyl-5-oxo-2-pyrazinyl]-2-methylphenyl]-4,5,6,7-tetrahydro-(GDC-0834); RN-486; Benzamide,4-(1,1-dimethylethyl)-N-[3-[8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl]phenyl]-(CGI-560);Benzamide,N-[3-[4,5-dihydro-4-methyl-6-[[4-(4-morpholinylcarbonyl)phenyl]amino]-5-oxo-2-pyrazinyl]-2-methylphenyl]-4-(1,1-dimethylethyl)-(CGI-1746CAS Registry No. 910232-84-7); HM-71224; 2-Propenamide,N-[3-[[5-fluoro-2-[[4-(2-methoxyethoxy)phenyl]amino]-4-pyrimidinyl]amino]phenyl]-(CC-292,CAS Registry No. 1202757-89-8); 2-Pyridinecarboxamide,4-[4-[[5-fluoro-4-[[3-[(1-oxo-2-propen-1-yl)amino]phenyl]amino]-2-pyrimidinyl]amino]phenoxy]-N-methyl-(CNX-774,CAS Registry No. 1202759-32-7), AVL-101 (CAS Registry No. 1552307-34-2),AVL-291 (CAS Registry No. 1552307-35-3), and AVL-292 (CAS Registry No.1552307-36-4), [N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide](dasatinib), alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-bromophenyl)propenamide (LFM-A13), and ONO-WG-307.

Inhibitors of osteoclast activity may be used for a number of medicalpurposes, such as treatment of undesirable conditions or diseases,including pain relief. This may be accomplished in many instances byadministration of oral dosage forms. Generally, an oral dosage formcomprising a bisphosphonate such as zoledronic acid is administeredorally to a mammal, such as a human being, at least once, to treat adisease or condition, or to relieve pain.

The following cations may also be in compounds that are osteoclastinhibitors:

The term “treating” or “treatment” broadly includes any kind oftreatment activity, including the diagnosis, cure, mitigation, orprevention of disease in man or other animals, or any activity thatotherwise affects the structure or any function of the body of man orother animals.

An oral dosage form of a bisphosphonate such as zoledronic acid may beused to treat, or provide relief of, any type of pain including, but notlimited to, inflammatory pain, arthritis pain, complex regional painsyndrome, lumbosacral pain, musculoskeletal pain, neuropathic pain,chronic pain, cancer-related pain, acute pain, postoperative pain, etc.In some instances, pain relief may be palliative, or pain relief may beprovided independent of improvement of the disease or condition or theunderlying cause of the disease or condition. For example, although theunderlying disease may not improve, or may continue to progress, anindividual suffering from the disease may experience pain relief. Insome embodiments, enhanced bioavailability of the zoledronic acid may beachieved in treating one of these conditions by administering a dosageform comprising zoledronic acid in the form of a disodium salt. This mayallow a reduced molar amount of the disodium salt to be used as comparedto what would be used with the diacid form.

In some embodiments, the mammal being treated is not suffering from bonemetastasis. In some embodiments, the mammal being treated is notsuffering from cancer. In some embodiments, the mammal being treated isnot suffering from osteoporosis.

For example, zoledronic acid or another bisphosphonate may beadministered orally to relieve musculoskeletal pain including low backpain, and pain associated with rheumatoid arthritis, juvenile rheumatoidarthritis, osteoarthritis, erosive osteoarthritis, sero-negative(non-rheumatoid) arthropathies, non-articular rheumatism, peri-articulardisorders, axial spondyloarthritis including ankylosing spondylitis,Paget's disease, fibrous dysplasia, SAPHO syndrome, transientosteoarthritis of the hip, vertebral crush fractures, osteoporosis, etc.In some embodiments, enhanced bioavailability of the zoledronic acid maybe achieved in treating one of these conditions by administering adosage form comprising zoledronic acid in the form of a disodium salt.This may allow a reduced molar amount of the disodium salt to be used ascompared to what would be used with the diacid form.

An osteoclast inhibitor, such as a bisphosphonate, e.g. zoledronic acid,may also be used to treat bone fractures or to enhance the healing ofbone fractures.

In some embodiments, zoledronic acid or another bisphosphonate may alsobe administered orally to relieve neuropathic pain, including diabeticperipheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia,monoradiculopathies, phantom limb pain, and central pain. Other causesof neuropathic pain include cancer-related pain, lumbar nerve rootcompression, spinal cord injury, post-stroke pain, central multiplesclerosis pain, HIV-associated neuropathy, and radio-therapy orchemo-therapy associated neuropathy. In some embodiments, enhancedbioavailability of the zoledronic acid may be achieved in treating oneof these conditions by administering a dosage form comprising zoledronicacid in the form of a disodium salt. This may allow a reduced molaramount of the disodium salt to be used as compared to what would be usedwith the diacid form.

In some embodiments, zoledronic acid or another bisphosphonate may beadministered orally to relieve inflammatory pain includingmusculoskeletal pain, arthritis pain, and complex regional painsyndrome. In some embodiments, enhanced bioavailability of thezoledronic acid may be achieved in treating one of these conditions byadministering a dosage form comprising zoledronic acid in the form of adisodium salt. This may allow a reduced molar amount of the disodiumsalt to be used as compared to what would be used with the diacid form.

Examples of musculoskeletal pain include low back pain; and painassociated with vertebral crush fractures, fibrous dysplasia,osteogenesis imperfecta, Paget's disease of bone, transientosteoporosis, and transient osteoporosis of the hip.

Arthritis refers to inflammatory joint diseases that can be associatedwith pain. Examples of arthritis pain include pain associated withosteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenilerheumatoid arthritis, sero-negative (non-rheumatoid) arthropathies,non-articular rheumatism, peri-articular disorders, neuropathicarthropathies including Charcot's foot, axial spondyloarthritisincluding ankylosing spondylitis, and SAPHO syndrome.

In some embodiments, a human being that is treated for a disease orcondition, such as an inflammatory condition, e.g. arthritis, by anosteoclast inhibitor, such as a bisphosphonate, e.g. an oral dosage formof zoledronic acid, has an age of about 10 years to about 90 years,about 20 years to about 80 years, about 30 years to about 75 years old,about 40 years to about 70 years, about 1 year to about 16 years, orabout 80 years to about 95 years.

In some embodiments, a human being that is treated for a disease orcondition, such as an inflammatory condition, e.g. arthritis, by anosteoclast inhibitor, such as a bisphosphonate, e.g. an oral dosage formof zoledronic acid, has suffered from the arthritis for at least 1month, at least 2 months, at least 6 months, or at least 1 year.

In some embodiments, the arthritis affects a knee, an elbow, a finger, awrist, a shoulder, an ankle, the spine, or a hip.

For treatment of arthritis or joint pain, such as knee pain, in someembodiments the person being treated has OARSI Grade 0, or Kellgren andLawrence Grades 0 or 1, joint space narrowing.

In some embodiments, the person has lesions, such as bone marrowlesions. In some embodiments the person being treated for bone marrowlesions has normal joint space knee pain, OARSI Grade 0, or Kellgren andLawrence Grades 0 or 1, joint space narrowing.

In some embodiments, the person has baseline pain intensity of 5 orgreater measured using the 0-10 numerical rating scale (NRS), or 50 mmor greater using the 100 mm visual analog scale (VAS). In someembodiments the person being treated for pain has normal joint spaceknee pain, OARSI Grade 0, or Kellgren and Lawrence Grades 0 or 1, jointspace narrowing.

Bone marrow lesions (BMLs) include regional bone marrow signal intensityalterations on magnetic resonance imaging (MRI). BMLs can be present inthe knee and can be an important feature of osteoarthritis of the knee.BMLs have also been described in other rheumatic conditions such asrheumatoid arthritis, osteonecrosis, ankylosing spondylitis, andtransient osteoporosis of the hip and are often referred to as bonemarrow edema (BME).

In some embodiments, a person being treated for arthritis, such as withzoledronic acid, has osteoarthritis of the knee associated with bonemarrow lesions.

In some embodiments, an inhibitor of osteoclast activity can be used totreat bone marrow lesions.

In some embodiments, an inhibitor of osteoclast activity can be used totreat bone marrow lesions of the knee, shoulder, ankle, wrist, hand,fingers, spine, or hip.

Commonly used measures of pain intensity include the visual analog scale(VAS) and the numerical rating scale (NRS). With the VAS approach,patients rate the severity of their pain by marking a point on a 10-cm(or 100 mm) VAS (0=no pain and 10=worst possible pain). With the NRSapproach, patients rate the severity of their pain by verballyresponding to a 10-point NRS (0=no pain and 10=worst possible pain). VASand NRS scores have been shown to be strongly correlated (slope ofregression line, 1.01), indicating that a score on the 10-cm VAS isequivalent to the same score on 10-point NRS (Bijur P E et al. AcadEmerg Med 2003; 10:390-392). For example, a VAS score of 5 cm (or 50 mm)is equivalent to an NRS score of 5. Knee pain in a person with a VASscore of 5 cm or 50 mm or higher, or an NRS score of 5 or higher, may bereferred to herein as moderate to severe knee pain.

In some embodiments, the patient suffering from pain, inflammation, asimilar condition, or any of the conditions described herein, has an NRSof 5 or greater, or a VAS of 5 cm or greater. In some embodiments, thepatient has an NRS of 4 or greater, or a VAS of 4 cm or greater. In someembodiments, the patient has an NRS of 6 or greater, or a VAS of 6 cm orgreater. In some embodiments, the patient has an NRS of 7 or greater, ora VAS of 7 cm or greater. In some embodiments, the patient has an NRS ofabout 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8,about 9, or about 10. In some embodiments, the patient has a VAS ofabout 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm,about 7 cm, about 8 cm, about 9 cm, or about 10 cm.

For knee pain or pain associated with bone marrow lesions, in someembodiments, treatment with a nitrogen-containing bisphosphonate such aszoledronic acid may decrease the visual analog (VAS) pain score measuredusing a 100 mm scale, by at least about 5 mm, at least about 8 mm, atleast about 10 mm, at least about 15 mm, up to about 50 mm, or up toabout 100 mm. In some embodiments, the VAS score, may be decreased by atleast about 5 mm, at least about 8 mm, at least about 10 mm, at leastabout 15 mm, up to about 50 mm, or up to about 100 mm, as compared to aplacebo.

Treatment with a nitrogen-containing bisphosphonate such as zoledronicacid may decrease the numerical rating scale (NRS) pain score measuredusing a 0-10 scale, by at least about 0.1, at least about 0.5, at leastabout 0.8, at least about 1, at least about 1.5, up to about 5, or up toabout 10. In some embodiments, the NRS score may be decreased by atleast about 0.1, at least about 0.5, at least about 0.8, at least about1, at least about 1.5, up to about 5, or up to about 10, as compared toa placebo.

In some embodiments, an inhibitor of osteoclast activity can be used toreduce the size of bone marrow lesions. The area of the lesions may bemeasured as the total area of all lesions or as the area of any onelesion. In some embodiments, the total area includes the medial tibialarea, the medial femoral area, the lateral tibial area, and the lateralfemoral area. In some embodiments the bone marrow lesion in located inthe patella.

In some embodiments, the use of an inhibitor of osteoclast activityachieves a reduction in the total area of the bone marrow lesions of atleast about 240 mm². In some embodiments, the reduction in total area isat least about 220 mm², at least about 200 mm², at least about 150 mm²,at least about 100 mm², or at least about 50 mm². In some embodiments,the reduction in size of bone marrow lesions represents a reductionrelative to baseline of at least about 10%, at least about 20%, at leastabout 30%, at least about 40%, at least about 50%, at least about 60%,at least about 70% at least about 80%, at least about 90%, or about100%. In some embodiments, the reduction in area of bone marrow lesionsrepresents an improvement relative to placebo of at least about 10%, atleast about 20%, at least about 30%, at least about 40%, at least about50%, at least about 60%, at least about 70%, at least about 80%, atleast about 90%, at least about 100%, at least about 120%, at leastabout 150%, at least about 170%, at least about 200%, at least about250%, at least about 300%, at least about 350%, at least about 400%, orat least about 450%. In some embodiments, the use of an inhibitor ofosteoclast activity inhibits an increase in the size of the bone marrowlesions over time.

Joint space narrowing (JSN) is typically graded using the OsteoarthritisResearch Society International (OARSI) atlas criteria, or the Kellgrenand Lawrence (K/L) system. The OARSI atlas criteria grades JSN using a0-3 scale with Grade 0 indicating an absence of JSN, and Grades 1, 2 and3 indicating mild, moderate, and severe JSN, respectively (Altman andGold, Osteoarthritis Cartilage 2007; 15(Suppl A):A1-A56). The K/L systemgrades JSN using a 0-4 scale with Grade 0 indicating an absence of JSN,Grade 1 indicating doubtful JSN, and grades 2, 3 and 4 indicatingminimal, moderate, and severe JSN, respectively (Kellgren and Lawrence,Ann Rheum Dis 1957; 16:494-502). Based on these criteria, OARSI Grade 0(absence of JSN), approximates K/L Grades 0-1 (absence of, or doubtfulpresence of JSN). Knee pain in a person having OARSI Grade 0 or K/LGrade or 1 JSN in the knee where the pain occurs may be referred toherein as a “normal joint space knee pain.”

In some embodiments for patients having OARSI Grade 0 or K/L Grades 0-1JSN, the use of an inhibitor of osteoclast activity achieves a reductionin the total area of the bone marrow lesions of at least about 240 mm².In some embodiments, the reduction in total area is at least about 220mm², at least about 200 mm², at least about 150 mm², at least about 100mm², or at least about 50 mm². In some embodiments, the reduction insize of bone marrow lesions represents a reduction relative to baselineof at least about 10%, at least about 15%, at least about 20%, at leastabout 25%, at least about 30%, at least about 35%, at least about 40%,at least about 45%, at least about 50%, at least about 60%, at leastabout 70% at least about 80%, at least about 90%, or about 100%. In someembodiments, the reduction in area of bone marrow lesions represents animprovement relative to placebo of at least about 10%, at least about20%, at least about 30%, at least about 40%, at least about 50%, atleast about 60%, at least about 70%, at least about 80%, at least about90%, at least about 100%, at least about 120%, at least about 150%, atleast about 170%, at least about 200%, at least about 250%, at leastabout 300%, at least about 350%, at least about 400%, or at least about450%. In some embodiments, the use of an inhibitor of osteoclastactivity inhibits an increase in the size of bone marrow lesions overtime.

In some embodiments for patients having OARSI Grades 1-2 or K/L Grades2-4 JSN, the use of an inhibitor of osteoclast activity achieves areduction in the total area of the bone marrow lesions of at least about100 mm². In some embodiments, the reduction in total area is at leastabout 50 mm², at least about 60 mm², at least about 80 mm², at leastabout 85 mm², at least about 90 mm², at least about 100 mm², at leastabout 105 mm², at least about 110 mm², or at least about 115 mm². Insome embodiments, the reduction in size of bone marrow lesionsrepresents a reduction relative to baseline of at least about 10%, atleast about 20%, at least about 30%, at least about 40%, at least about50%, at least about 60%, at least about 70% at least about 80%, at leastabout 90%, or about 100%. In some embodiments, the reduction in area ofbone marrow lesions represents an improvement relative to placebo of atleast about 10%, at least about 20%, at least about 30%, at least about40%, at least about 50%, at least about 60%, at least about 70%, atleast about 80%, at least about 90%, at least about 100%, at least about115%, at least about 125%, at least about 135%, at least about 150%, atleast about 170%, at least about 200%, at least about 250%, at leastabout 300%, at least about 350%, at least about 400%, or at least about450%. In some embodiments, the use of an inhibitor of osteoclastactivity inhibits an increase in the size of bone marrow lesions overtime.

In some embodiments, an inhibitor of osteoclast activity, such as anitrogen-containing bisphosphonate, including e.g. zoledronic acid,minodronic acid, etc., is used to treat fibromyalgia.

According to some embodiments, administration of an inhibitor ofosteoclast activity achieves a reduction in pain that lasts at leastabout one month, two months, three months, four months, six months, oreven at least about 12 months. According some embodiments,administration of an inhibitor of osteoclast activity achieves areduction in pain that is observed at greater than three hours, at aboutone day, at about two to about five days, at about one week, at abouttwo weeks, at about three weeks, at about one month, at about fiveweeks, at about six weeks, at about seven weeks, at about two months, atabout nine weeks, at about ten weeks, at about eleven weeks, at aboutthree months, at about four months, at about six months, or at about 12months after administration of the inhibitor of osteoclast activity.

According some embodiments, administration of an inhibitor of osteoclastactivity achieves a reduction in pain that is observed at greater thanthree hours, but at or before one week, two weeks, three weeks, fourweeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, 10weeks, 11 weeks, 12 weeks, four months, five months, or six months.

According some embodiments, administration of an inhibitor of osteoclastactivity achieves a reduction in pain that is observed at greater thanthree hours with a duration of no more than about three months, no morethan about four months, no more than about five months, or no more thanabout six months.

According to some embodiments, after the administration of an inhibitorof osteoclast activity, the area of bone marrow lesions relative to thesize prior to administration remains reduced for up to three months,four months, five months, six months, or even up to 12 months or more.According to some embodiments, after the administration of an inhibitorof osteoclast activity, the area of bone marrow lesions relative to thesize prior to administration is reduced at about three months, at aboutfour months, at about five months, at about six months, or at about 12months.

According to some embodiments, after administration of an inhibitor ofosteoclast activity, the size of Modic changes or VESCs relative to thesize prior to administration remains reduced for up to three months,four months, five months, six months, or even up to 12 months or more.According to some embodiments, after the administration of an inhibitorof osteoclast activity, the size of Modic changes or VESCs relative tothe size prior to administration is reduced at about three months, atabout four months, at about five months, at about six months, or atabout 12 months.

In some embodiments, an osteoclast inhibitor, such as anitrogen-containing bisphosphonate, e.g. zoledronic acid, ibandronicacid or minodronic acid, may be administered to relieve complex regionalpain syndrome, such as complex regional pain syndrome type I (CRPS-I),complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or anothertype of CRPS.

In some embodiments, zoledronic acid or another bisphosphonate may beadministered orally to relieve complex regional pain syndrome, such ascomplex regional pain syndrome type I (CRPS-I), complex regional painsyndrome type II (CRPS-II), CRPS-NOS, or another type of CRPS. CRPS is atype of inflammatory pain. CRPS can also have a neuropathic component.

Complex regional pain syndrome is a debilitating pain syndrome. It ischaracterized by severe pain in a limb that can be accompanied by edema,and autonomic, motor and sensory changes.

In some embodiments, an osteoclast inhibitor, such as anitrogen-containing bisphosphonate, e.g. zoledronic acid or minodronicacid, may be used to reduce the use of non-steroidal anti-inflammatorydrug (NSAIDs), opioids, or other pain medications, for a patientsuffering from pain, inflammation, a similar condition, or any conditiondescribed herein. For example, use of NSAIDs, opioids, or other painmedications may be reduced by at least about 5%, at least about 10%, atleast about 15%, at least about 20%, at least about 25%, at least about30%, at least about 35%, at least about 40%, at least about 45%, atleast about 50%, at least about 60%, at least about 70%, at least about80%, or at least about 90%, up to about 100%, as compared to the use ofNSAIDs, opioids or other pain medications without administration of theosteoclast inhibitor. Use of the opioids, NSAIDs, or other painmedications may be reduced by at least about 5%, at least about 10%, atleast about 15%, at least about 20%, at least about 25%, at least about30%, at least about 35%, at least about 40%, at least about 45%, atleast about 50%, at least about 60%, at least about 70%, at least about80%, or at least about 90%, up to about 100%, as compared to the use ofNSAIDS, opioids, or other pain medications at baseline.

The reduction in the use of NSAIDs, opioids, or other pain medicationsmay be observed at about one week, about two weeks, about three weeks,about one month, about two months, about three months, about fourmonths, about five months, about six months, about seven months, abouteight months, about nine months, about 10 months, about 11 months, orabout one year or more, after the administration of osteoclastinhibitor.

With respect to use of oral zoledronic acid for relieving painassociated with an inflammatory condition, relief of pain can beshort-term, e.g. for a period of hours after administration of thedosage form, and/or relief of pain can be long-term, e.g. lasting fordays, weeks, or even months after oral administration of zoledronicacid. In some embodiments, a mammal, such as a human being, experiencessignificant pain relief at least about 3 hours, at least about 6 hours,at least about 12 hours, at least about 24 hours, at least about 48hours, at least about one week, at least about 2 weeks, or at leastabout 3 weeks after administration of an oral dosage form comprisingzoledronic acid. In some embodiments, a mammal, such as a human being,experiences significant pain relief during at least part of the timefrom about 3 hours to about 2 weeks, about 3 hours to about 3 weeks,about 3 hours to about 24 hours, about 6 hours to about 2 weeks, orabout 6 hours to about 24 hours, about 3 days to about 2 weeks, about 6days to about 2 weeks, after administration of an oral dosage formcomprising zoledronic acid. In some embodiments, a human being treatedhas significant pain relief at three months, six months, nine months, orone year after administration of the most recent dose of an osteoclastinhibitor such as zoledronic acid.

With respect to the treatment of any condition recited herein, in someembodiments a first oral dosage form comprising zoledronic acid isadministered and a second oral dosage form comprising oral zoledronicacid is administered. The timing of the administration of the two dosageforms may be such that, with respect to the first oral dosage form, thesecond oral dosage with respect to the first oral dosage form, thesecond oral dosage form is administered at 5×T_(max) or greater (e.g.,if T_(max) is 1 hour, at 5 hours or later), at least 10×T_(max) orgreater, at least about 15×T_(max) or greater, at least about 20×T_(max)or greater, at least about 50×T_(max) or greater, or at least about200×T_(max) or greater, wherein T_(max) is the time of maximum plasmaconcentration for the first oral dosage

Some embodiments include treatment of a condition recited herein, suchas inflammatory pain, arthritis, or complex regional pain syndrome,wherein the treatment comprises either: administering only one dosageform to a mammal to treat the condition, or administering a first dosageform to the mammal, followed by administering a second dosage form tothe mammal. If two or more dosage forms are administered, the secondoral dosage form is administered before the maximum pain relievingeffect of the first oral dosage form is achieved, or before a peak inthe pain relieving effect of the first oral dosage form is experiencedby a mammal, receiving the dosage form. In some embodiments, the secondoral dosage form is administered before an observable pain relievingeffect is achieved. In some embodiments, the second dosage form isadministered about 12 hours to about 60 days, about 24 hours to about 28days, about 24 hours to about 7 days, about 24 hours to about 14 days,or about 24 hours to about 21 days, after the first dosage form isadministered.

Some embodiments include treatment of a condition recited herein, suchas inflammatory pain, arthritis, or complex regional pain syndrome,wherein the treatment comprises administering a first dosage form to themammal, followed by administering a second dosage form to the mammal,wherein the second dosage form is administered after the maximum painrelieving effect of the first oral dosage form is achieved, and thesecond oral dosage form is administered while the mammal is stillexperiencing pain relief from the first oral dosage form, or while thepain relieving effect from the first oral dosage form is observable. Insome embodiments, the second dosage form is administered about 12 hoursto about 60 days, about 24 hours to about 28 days, about 24 hours toabout 7 days, about 24 hours to about 14 days, or about 24 hours toabout 21 days, after the first dosage form is administered.

Zoledronic acid or another bisphosphonate may also be administeredorally to relieve cancer-related pain, including pain associated withmultiple myeloma and bone metastases from solid tumors. In someembodiments, zoledronic acid is used to treat pain that is notcancer-related pain. For example, zoledronic acid may be used to treatpain that is not associated with multiple myeloma, bone metastasis fromsolid tumors, hypercalcemia of malignancy, giant cell tumor of bone,blood cancers or leukemias, or solid tumors or cancers. In someembodiments, enhanced bioavailability of the zoledronic acid may beachieved in treating one of these conditions by administering a dosageform comprising zoledronic acid in the form of a disodium salt. This mayallow a reduced molar amount of the disodium salt to be used as comparedto what would be used with the diacid form.

In addition to relieving pain, oral administration of zoledronic acid oranother bisphosphonate may also be useful to treat diseases orconditions that may or may not include a pain component. For example,zoledronic acid or another bisphosphonate may be useful to treat any ofthe pain conditions or types of conditions listed above, includingtreatment that does not simply relieve the pain of those conditions, andtreatment that is carried out in such a way that the condition istreated without pain relief occurring. In addition to any pain reliefzoledronic acid or another bisphosphonate may or may not provide,zoledronic acid or another bisphosphonate may be used to treat a diseaseor condition such as a metabolic disease or condition; an inflammatorydisease or condition, including an inflammatory disease or conditionthat is not associated with pain; a cancer disease or condition; aneurological disease or condition; etc. In some embodiments, enhancedbioavailability of the zoledronic acid may be achieved in treating oneof these conditions by administering a dosage form comprising zoledronicacid in the form of a disodium salt. This may allow a reduced molaramount of the disodium salt to be used as compared to what would be usedwith the diacid form.

In some embodiments, oral administration of zoledronic acid or anotherbisphosphonate may also be useful to treat complex regional painsyndrome, rheumatoid arthritis, osteoarthritis, erosive osteoarthritis,axial spondyloarthritis including ankylosing spondylitis, acutevertebral crush fracture, fibrous dysplasia, SAPHO syndrome,osteoporosis, transient osteoporosis, or transient osteoporosis of thehip. In some embodiments, enhanced bioavailability of the zoledronicacid may be achieved in treating one of these conditions byadministering a dosage form comprising zoledronic acid in the form of adisodium salt. This may allow a reduced molar amount of the disodiumsalt to be used as compared to what would be used with the diacid form.

In some embodiments, oral administration of zoledronic acid or anotherbisphosphonate may also be useful to treat hypercalcemia of malignancy,multiple myeloma, bone metastases from solid tumors, Paget's disease ofbone, giant cell tumor of bone, blood cancers or leukemias, or solidtumors or cancers. In some embodiments, enhanced bioavailability of thezoledronic acid may be achieved in treating one of these conditions byadministering a dosage form comprising zoledronic acid in the form of adisodium salt. This may allow a reduced molar amount of the disodiumsalt to be used as compared to what would be used with the diacid form.

Some nitrogen-containing bisphosphonates may be represented by FormulaA:

With respect to Formula A, R¹ is F, Cl, Br, H, or OH. In someembodiments, R¹ is OH.

With respect to Formula A, R² is aminoalkyl, such as aminoethyl,aminopropyl, aminopentyl, dimethylaminoethyl, methylpentylaminoethyl,etc; or optionally substituted heterocyclyl alkyl, such as optionallysubstituted imidazolylmethyl, optionally substituted pyridinymethyl,etc. In some embodiments R² is optionally substituted imidazolylalkyl.

Unless otherwise indicated, when a compound or chemical structuralfeature such as heterocyclyl alkyl is referred to as being “optionallysubstituted,” it includes a feature that has no substituents (i.e.unsubstituted), or a feature that is substituted, meaning that thefeature has one or more substituents. The term “substituent” has thebroadest meaning known to one of ordinary skill in the art, and includesa moiety that replaces one or more hydrogen atoms in a parent compoundor structural feature. The term “replaces” is merely used herein forconvenience, and does not require that the compound be formed byreplacing one atom with another. In some embodiments, a substituent maybe any ordinary organic moiety known in the art, which may have amolecular weight (e.g. the sum of the atomic masses of the atoms of thesubstituent) of 15 g/mol to 50 g/mol, 15 g/mol to 100 g/mol, 15 g/mol to150 g/mol, 15 g/mol to 200 g/mol, 15 g/mol to 300 g/mol, or 15 g/mol to500 g/mol. In some embodiments, a substituent comprises, or consists of:0-30, 0-20, 0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0-10, or 0-5heteroatoms, wherein each heteroatom may independently be: N, O, P, S,Si, F, Cl, Br, or I; provided that the substituent includes one C, N, O,P, S, Si, F, Cl, Br, or I atom. In some embodiments, substituents canindependently have a molecular weight of about 15 Da to about 600 Da andcan consist of 2 to 5 chemical elements, wherein the chemical elementsare independently C, H, O, N, P, S, Si, F, Cl, or Br. In someembodiments, a substituent is optionally substituted alkyl, —O-alkyl(e.g. —OCH₃, —OC₂H5, —OC₃H₇, —OC₄H₉, etc.), —S-alkyl (e.g. —SCH₃,—SC₂H₅, —SC₃H₇, —SC₄H₉, etc.), —NR′R″, —OH, —SH, —CN, —CF₃, —NO₂,perfluoroalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted amine or a halogen, wherein R′ and R″are independently H or optionally substituted alkyl. Wherever asubstituent is described as “optionally substituted,” that substituentcan be substituted with the above substituents.

For convenience, the term “molecular weight” is used with respect to amoiety or part of a molecule to indicate the sum of the atomic masses ofthe atoms in the moiety or part of a molecule, even though it may not bea complete molecule.

Examples of nitrogen-containing bisphosphonates include but are notlimited to pamidronic acid, incadronic acid, ibandronic acid, risedronicacid, minodronic acid, cimadronic acid, neridronic acid, alendronicacid, olpadronic acid, zoledronic acid, etc.

Zoledronic acid has the structure shown below, and is also referred toas zoledronate.

Unless otherwise indicated, any reference to a compound herein, such aszoledronic acid, by structure, name, or any other means, includespharmaceutically acceptable salts, such as the disodium salt; alternatesolid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; orany other chemical species that may rapidly convert to a compounddescribed herein under conditions in which the compounds are used asdescribed herein.

In some embodiments, zoledronic acid is administered in a dosage formcomprising a salt form, such as a salt of a dianion of zoledronic acid.In some embodiments, zoledronic acid is administered in a dosage formcomprising a disodium salt form of zoledronic acid. In some embodiments,zoledronic acid is administered in a sodium salt form, such as amonosodium salt, a disodium salt, a trisodium salt, etc. In somecircumstances, use of the disodium salt may be desirable. For example,the disodium salt is much more soluble in water than the diacid form. Asa result, in some processes, the disodium salt can be easier to workwith than the diacid form. Additionally, the sodium salt may be morebioavailable and/or more rapidly absorbed when taken orally as comparedto the diacid form.

Examples of salts of Compound 1 are shown below:

wherein X⁻ is any suitable anion, e.g. F⁻, Br⁻, Cl⁻, I⁻, OH⁻, acetate,etc.; and M⁺ is any suitable cation, e.g. Na⁺, K⁺, NH₄ ⁺, etc. Manyother salt forms are also possible.

In some embodiments, Compound 1 may be further represented by a formula,

In some embodiments, Compound 1 may be in a hydrate form.

In some embodiments, Compound 1 is administered in a dosage formcomprising a salt form, such as a zwitterionic form, or a salt of acation, a monoanion, a dianion, a trianion, etc., of Compound 1.

Compound 1 can be present in any amount, such as less than about 100%w/w, less than about 50% w/w, less than about 20% w/w, less than about10% w/w, less than about 1% w/w, less than 0.1% w/w, less than about0.07% w/w, less than about 0.05% w/w, less than about 0.04% w/w, lessthan about 0.03% w/w, less than about 0.02% w/w; and/or greater than 0%w/w, at least about 0.00000001% w/w, at least about 0.000001% w/w, or atleast about 0.00001% w/w, based upon the total amount of zoledronicacid, Compound 1, and Compound 2 present in the composition.

Examples of salts of Compound 2 are shown below:

wherein X⁻ is any suitable anion, e.g. F⁻, Br⁻, Cl⁻, I⁻, OH⁻, acetate,etc.; and M⁺ is any suitable cation, e.g. Na⁺, K⁺, NH₄ ⁺, etc. Manyother salt forms are also possible.

In some embodiments, a salt of compound 2 may be further represented bya formula,

In some embodiments, compound 2 may be in a hydrate form.

In some embodiments, Compound 2 is administered in a dosage formcomprising a salt form, such as a zwitterionic form, or a salt of acation, a monoanion, a dianion, a trianion, etc., of Compound 2.

Compound 2 can be present in any amount, such as less than about 100%w/w, less than about 50% w/w, less than about 20% w/w, less than about10% w/w, less than about 1% w/w, less than about 0.3%, less than about0.2%, less than 0.1% w/w, less than about 0.08% w/w, less than about0.07% w/w, less than about 0.05% w/w, less than about 0.04% w/w, lessthan about 0.03% w/w, less than about 0.02% w/w; and/or greater than 0%w/w, at least about 0.00000001% w/w, at least about 0.000001% w/w, or atleast about 0.00001% w/w, based upon the total amount of zoledronicacid, Compound 1, and Compound 2 present in the composition.

In some embodiments, Compound 1 and Compound 2 are present in an amountthat is less than 0.1% w/w.

In some embodiments, the administration of an osteoclast inhibitor, suchas a nitrogen-containing bisphosphonate, including, e.g. zoledronicacid, minodronic acid, etc., to a patient or mammal in need thereofaffects Modic changes (MCs). For example, any of the above compoundscould be used to treat Modic changes, or vertebral endplate signalchanges (VESC) and bone marrow changes visible using magnetic resonanceimaging (MRI), or neck pain or back pain associated with Modic changes.

Modic changes, as used herein, includes its ordinary meaning in the artand refers to pathological vertebral endplate and bone marrow changesvisible using magnetic resonance imaging (MRI). Modic changes may alsobe referred to as vertebral endplate signal changes (VESC). Modicchanges, can be classified into various types including type 1 (M1),type 2 (M2), and type 3 (M3) lesions or changes, any of which may betreated using an osteoclast inhibitor, such as anitrogen-bisphosphonate, including, e.g. zoledronic acid, minodronicacid, etc. Different types of Modic changes may occur in the samepatient, for example type 1 and type 2 Modic changes (M1/2). In somecases, M1 changes are related to lower back pain than other types ofModic change.

VESCs may be found in patients with different types of low back painincluding but not limited to spondylitis, trauma, spondyloarthropathiesincluding ankylosing spondylitis, Schmorl's nodes, fracture, tumor, andspinal cord infarction. Lesions in ankylosing spondylitis includeosteitis and spondylodiscitis, which can be detected using MRI oranother medical imaging instrument.

Modic changes may be found in the cervical, thoracic, lumbar, and sacralspine. Modic changes may be found at various spinal levels such as atC1/2, C2/3, C3/4, C4/5, C5/6, C6/7, C7/T1, T1/2, T2/3, T3/4, T4/5, T5/6,T6/7, T7/8, T8/9, T9/10, T10/11, T11/12, T12/L1, L1/2, L2/3, L3/4, L4/5,L5/S1, etc., any of which may be treated using an osteoclast inhibitor,such as a nitrogen-bisphosphonate, including, e.g. zoledronic acid,minodronic acid, etc.

In some embodiments, the Modic change being treated is located at L2/3.In some embodiments, the Modic change being treated is located at L3/4.In some embodiments, the Modic change being treated is located at L4/5.In some embodiments, the Modic change being treated is located at L5/S1.

In some embodiments, the Modic change being treated is located at C3/4.In some embodiments, the Modic change being treated is located in atC4/5. In some embodiments, the Modic change being treated is located inat C5/6. In some embodiments, the Modic change being treated is locatedin at C6/7.

In some embodiments, the Modic change being treated is located at T5/6.In some embodiments, the Modic change being treated is located in atT6/7. In some embodiments, the Modic change being treated is located inat T7/8. In some embodiments, the Modic change being treated is locatedin at T8/9. In some embodiments, the Modic change being treated islocated at T9/10.

In some embodiments, the patient being treated has predominantly M1. Insome embodiments, the patient being treated has predominantly M1/M2. Insome embodiments, the patient being treated has predominantly M2. Insome embodiments, the patient being treated has predominantly M3.

In some embodiments, the worst type of lesion that the patient beingtreated has is M1. In some embodiments, the worst type of lesion thatthe patient being treated has is M1/2. In some embodiments, the worsttype of lesion that the patient being treated has is M2.

In some embodiments, the patient being treated has Modic changes at moretwo or more levels. In some embodiments the patient being treated hasModic changes at three or more levels. In some embodiments greater painrelief is obtained when treating a patient with Modic changes at twolevels, or three or more levels, than is obtained when treating apatient with Modic changes at a single level or at two levels.

In some embodiments greater pain relief is obtained when treating apatient with Modic changes at two levels than is obtained when treatinga patient with Modic changes at a single level.

In some embodiments greater pain relief is obtained when treating apatient with Modic changes at three or more levels than is obtained whentreating a patient with Modic changes at a single level.

In some embodiments greater pain relief is obtained when treating apatient with Modic changes three or more levels than is obtained whentreating a patient with Modic changes at two levels.

In some embodiments, the inhibitor of osteoclast activity may be used toeffect a reduction in the levels of pro-inflammatory cytokines in thepatient with low back pain or any other type of pain or conditionrecited herein. In some embodiments greater pain relief may be obtainedin patients with greater baseline levels of pro-inflammatory cytokineswhen treated with an inhibitor of osteoclast activity, such as anitrogen-containing bisphosphonate, including e.g. zoledronic acid,minodronic acid, etc. In some embodiments, greater pain relief may beobtained in patients who experience a reduction or a greater reductionin the levels of pro-inflammatory cytokines when treated with aninhibitor of osteoclast activity, such as a nitrogen-containingbisphosphonate, including e.g. zoledronic acid, minodronic acid, etc.Pro-inflammatory cytokines include but are not limited to IL-1, IL-2,IL-3, IL-6, IL-8, IL-10, IL-12, tumor necrosis alpha (TNF-alpha),interferon gamma, etc.

In some embodiments, the use of an inhibitor of osteoclast activity,such as a nitrogen-containing bisphosphonate, including e.g. zoledronicacid, minodronic acid, etc., to a patient or mammal in need thereof,achieves a reduction relative to baseline in the size of Modic changesor VESCs of at least about 5%, at least about 10%, at least about 15%,at least about 20%, at least about 25%, at least about 30%, at leastabout 40%, at least about 50%, at least about 60%, at least about 70% atleast about 80%, at least about 90%, or about 100%. In some embodiments,the reduction the size of Modic changes or VESCs represents animprovement relative to placebo of at least about 10%, at least about15%, at least about 20%, at least about 25%, at least about 30%, atleast about 40%, at least about 50%, at least about 60%, at least about70%, at least about 80%, at least about 90%, at least about 100%, atleast about 120%, at least about 150%, at least about 170%, at leastabout 200%, at least about 250%, at least about 300%, at least about350%, at least about 400%, or at least about 450%. In some embodiments,the use of an inhibitor of osteoclast activity inhibits an increase inthe size of Modic changes or VESCs over time.

The oral bioavailability of zoledronic acid may be enhanced by orallyadministering the zoledronic acid in the disodium salt form. Forexample, the bioavailability of zoledronic acid may be improved by atleast about 10%, at least about 20%, at least about 30%, at least about50%, and/or up to about 100%, or up to about 200%, as compared toadministration of zoledronic acid in the diacid form.

Because of the improved bioavailability of the disodium salt a dosageform may contain, or a mammal, such as a human being, may receive, on amolar basis, less of the disodium salt form of zoledronic acid thanwould otherwise be administered of the diacid form of zoledronic acid.For example, a dosage form may contain, or a mammal may receive, atleast about 10 mole % less, at least about 20 mole % less, at leastabout 40 mole % less, at least about 50 mole % less, and/or up to about90 mole % less or 95 mole % less, of the disodium salt form as comparedthe amount of the diacid form of zoledronic acid that would otherwise beadministered, such as a molar amount that would be administered ofzoledronic acid in the diacid form in order to achieve the same plasmalevels of zoledronic acid.

In some embodiments, a dosage form contains, or a mammal (such as ahuman being) is administered, an amount of the disodium salt form, on amolar basis, that has a value of about 0.8n_(d) to about 1.2n_(d) orabout 0.9n_(d) to about 1.1 n_(d), wherein:

n _(d)=(b _(a) /b _(d))(n _(a))

wherein b_(a) is the bioavailability of the diacid form, b_(d) is thebioavailability of the disodium salt form, and n_(a) is the number ofmoles of the diacid that would be administered in a dosage formcontaining the diacid form of zoledronic acid. For example, if thediacid form has a bioavailability (b_(a)) of 0.01 and the disodium saltform has a bioavailabity (b_(d)) of 0.015, and a dosage form wouldnormally contain 0.001 moles of the diacid, n_(d) would be(0.01/0.015)(0.001 moles), or about 0.00067 moles. In some embodiments,the disodium salt is administered in an amount that has a value of aboutn_(d).

With respect to oral dosage forms comprising a reduced molar amount ofthe disodium salt of zoledronic acid as compared to the diacid form ofzoledronic acid, in some embodiments, the bioavailability of thezoledronic acid in the disodium salt form is sufficiently high that, ifthe drug is administered to a mammal, at least as much zoledronic acidis present in the blood of the mammal as would be present if zoledronicacid were administered in the diacid form.

With respect to oral dosage forms comprising the disodium salt form ofzoledronic acid, in some embodiments, the disodium salt form is presentin a lower molar amount than would be present if the zoledronic acidwere in the diacid form; and the zoledronic acid in the disodium saltform has an improved bioavailability as compared to the zoledronic acidin the diacid form to the extent that the lower molar amount of thedisodium salt in the dosage form does not reduce the amount ofzoledronic acid delivered to the plasma of a mammal.

Some oral dosage forms comprising zoledronic acid have a dose ofzoledronic acid and a configuration suitable for a particular species ofmammal, e.g. dog, rat, human, etc. Such a dosage form may havezoledronic acid present in an amount that results in a desired range foran area under the plasma concentration curve (AUC) of zoledronic acid inthat particular species of mammal. For example the dose of zoledronicacid and a configuration of the oral dosage form may result in an AUC ofzoledronic acid of about 1 ng·hr/mL to about 700 ng·hr/mL, about 3ng·hr/mL to about 30 ng·hr/mL, about 3 ng·hr/mL to about 10 ng·hr/mL,about 50 ng·hr/mL to about 700 ng·hr/mL, about 130 ng·hr/mL to about 180ng·hr/mL, about 300 ng·hr/mL to about 450 ng·hr/mL, about 300 ng·hr/mLto about 350 ng·hr/mL, about 300 ng·hr/mL to about 310 ng·hr/mL, about340 ng·hr/mL to about 350 ng·hr/mL, about 370 ng·hr/mL to about 420ng·hr/mL, about 380 ng·hr/mL to about 390 ng·hr/mL, about 405 ng·hr/mLto about 415 ng·hr/mL, about 140 ng·hr/mL to about 160 ng·hr/mL, about140 ng·hr/mL to about 150 ng·hr/mL, about 150 ng·hr/mL to about 160ng·hr/mL, about 140 ng·hr/mL, 142 ng·hr/mL, about 155 ng·hr/mL, about305 ng·hr/mL, 304 ng·hr/mL, about 345 ng·hr/mL, 343 ng·hr/mL, about 385ng·hr/mL, 384 ng·hr/mL, about 410 ng·hr/mL, or any AUC in a rangebounded by, or between, any of these values, upon administration of theoral dosage form to a mammal.

Unless otherwise indicated, the AUC refers to the AUC calculated to thelast measured concentration (AUC_((0-t)) and extrapolated to infinity(AUC_((0-inf))).

An oral dosage form comprising zoledronic acid having a dose ofzoledronic acid and a configuration suitable for a particular species ofmammal may have zoledronic acid present in an amount that results in aC_(max) of zoledronic acid of about 0.2 ng/mL to about 300 ng/mL, about0.5 ng/mL to about 5 ng/mL, about 5 ng/mL to about 300 ng/mL, about 5ng/mL to about 50 ng/mL, about 20 ng/mL to about 50 ng/mL, about 30ng/mL to about 50 ng/mL, about 50 ng/mL to about 200 ng/mL, about 50ng/mL to about 150 ng/mL, about 80 ng/mL to about 120 ng/mL, about 90ng/mL to about 100 ng/mL, about 50 ng/mL to about 200 ng/mL, about 40ng/mL, about 95 ng/mL, about 97 ng/mL, or any C_(max) in a range boundedby, or between, any of these values, upon administration of the oraldosage form to a mammal.

An oral dosage form comprising zoledronic acid having a dose ofzoledronic acid and a configuration suitable for a particular species ofmammal may be configured so that administration of the oral dosage formto the particular species of mammal results in a T_(max) of zoledronicacid of about 0.4 hr to about 1 hr, about 0.5 hr, or about 0.75 hr, orany T_(max) in a range bounded by, or between, any of these values.

In some embodiments, the zoledronic acid in the disodium salt form ispresent in an amount such that the oral dosage form provides an areaunder the plasma concentration curve of zoledronic acid of about 4ng·h/mL to about 2000 ng·h/mL to the mammal each time the zoledronicacid in the disodium salt is administered.

In some embodiments, the zoledronic acid is present in an amount suchthat the oral dosage form provides an area under the plasmaconcentration curve of zoledronic acid of about 100 ng·h/mL to about2000 ng·h/mL, about 100 ng·h/mL to about 1000 ng·h/mL, about 500 ng·h/mLto about 1000 ng·h/mL, or about 500 ng·h/mL to about 700 ng·h/mL in themammal to which the dosage form is administered. This amount may besuitable for administration of the oral dosage form about every 3 to 4weeks.

In some embodiments, the zoledronic acid is present in an amount suchthat the oral dosage form provides an area under the plasmaconcentration curve of zoledronic acid of about 20 ng·h/mL to about 700ng·h/mL, about 50 ng·h/mL to about 500 ng·h/mL, about 50 ng·h/mL toabout 400 ng·h/mL, about 50 ng·h/mL to about 300 ng·h/mL, about 50ng·h/mL to about 200 ng·h/mL, about 100 ng·h/mL to about 500 ng·h/mL,about 100 ng·h/mL to about 400 ng·h/mL, about 100 ng·h/mL to about 300ng·h/mL, about 100 ng·h/mL to about 200 ng·h/mL, about 125 ng·h/mL toabout 500 ng·h/mL, about 125 ng·h/mL to about 400 ng·h/mL, about 125ng·h/mL to about 300 ng·h/mL, about 125 ng·h/mL to about 200 ng·h/mL, orabout 200 ng·h/mL to about 300 ng·h/mL, in the mammal to which thedosage form is administered. This amount may be suitable for weeklyadministration of the oral dosage, or for administration of 3 to 5individual dosages during a month. The individual dosages could be givenat regular intervals, given during the first week, or at any otherschedule that provides 3 to 5 dosages during the month.

In some embodiments, the zoledronic acid is present in an amount suchthat the oral dosage form provides an area under the plasmaconcentration curve of zoledronic acid of about 4 ng·h/mL to about 100ng·h/mL, about 10 ng·h/mL to about 50 ng·h/mL, about 10 ng·h/mL to about30 ng·h/mL, 20 ng·h/mL to about 700 ng·h/mL, about 50 ng·h/mL to about500 ng·h/mL, about 50 ng·h/mL to about 400 ng·h/mL, about 50 ng·h/mL toabout 300 ng·h/mL, about 50 ng·h/mL to about 200 ng·h/mL, about 100ng·h/mL to about 500 ng·h/mL, about 100 ng·h/mL to about 400 ng·h/mL,about 100 ng·h/mL to about 300 ng·h/mL, about 100 ng·h/mL to about 200ng·h/mL, about 125 ng·h/mL to about 500 ng·h/mL, about 125 ng·h/mL toabout 400 ng·h/mL, about 125 ng·h/mL to about 300 ng·h/mL, about 125ng·h/mL to about 200 ng·h/mL, or about 200 ng·h/mL to about 300 ng·h/mLin the mammal to which the dosage form is administered. This amount maybe suitable for daily administration of the oral dosage form. In someembodiments, the dosage form may be administered for 2, 3, 4, 5, 6, 7,8, 9, or 10, 5 to 10, or 6 to 10 consecutive days.

Oral administration of zoledronic acid, particularly oral administrationof the disodium salt form of zoledronic acid, can result in moresustained plasma levels of the drug as compared to parenteral modes ofadministration, such intravenous or subcutaneous. For example, theamount of zoledronic acid in the plasma can be significantly higher fororal administration of the disodium salt about 24 hours or 48 hours, orlonger, after administration. In some embodiments, oral zoledronic acidhas a 24 hour sustained plasma level factor of about 1 or higher, suchas about 1 to about 10, about 1 to about 5, about 3 to about 5, or about3 to about 4. In some embodiments, an orally administered dosage form ofzoledronic acid has a 24 hour sustained plasma level factor or a 48 hoursustained plasma level factor that is higher, such as at least 1.2times, at least about 2 times, at least about 5 times, about 1.2 timesto about 20 times, about 2 times to about 15 times, about 5 times toabout 10 times, or about 8 to about 15 times that of intravenouslyadministered zoledronic acid. A “sustained plasma level factor,” p_(f),is determined by the equation:

p _(f)=1000(C _(t) /C _(max))

wherein C_(max) is the maximum plasma concentration of zoledronic acidafter it is administered and C_(t) is the plasma concentration ofzoledronic acid at the time of interest, such as 24 hours. Forparenteral administration, the C_(max) can be about the C₀, or theconcentration right after injection of the entire amount of the druginto the body. Sustained plasma level factors can also be obtained forother times, such as 48 hours, by using the plasma concentration ofzoledronic acid for C_(t) in the equation above. For example, if themaximum plasma level of zoledronic acid after administration is 1000ng/mL and the plasma level of zoledronic acid at 24 hours is 1 ng/mL,the 24 hour sustained plasma level factor is 1.

An oral dosage form comprising zoledronic acid having a dose ofzoledronic acid and a configuration suitable for a particular species ofmammal may be configured so that the zoledronic acid has a 12 hoursustained plasma level factor of about 12 to about 50, about 20 to about40, about 25 to about 30, about 30 to about 35, about 35 to about 40,about 33, about 30, about 35, or any 12 hour sustained plasma levelfactor in a range bounded by, or between, any of these values, for theparticular species of mammal.

An oral dosage form comprising zoledronic acid having a dose ofzoledronic acid and a configuration suitable for a particular species ofmammal may be configured so that the zoledronic acid has a 24 hoursustained plasma level factor of about 10 to about 30, about 10 to about20, about 10 to about 15, about 12 to about 15 or 16, about 15 to about20, about 14, about 12, about 15, or any 24 hour sustained plasma levelfactor in a range bounded by, or between, any of these values, for theparticular species of mammal.

An oral dosage form comprising zoledronic acid having a dose ofzoledronic acid and a configuration suitable for a particular species ofmammal may be configured so that the zoledronic acid has a 36 hoursustained plasma level factor of about 6 to about 20, about 8 to about15, about 9 to about 12 or 13, about 8 to about 10, about 11 to about13, about 9, about 13, or any 24 hour sustained plasma level factor in arange bounded by, or between, any of these values, for the particularspecies of mammal.

An oral dosage form comprising zoledronic acid having a dose ofzoledronic acid and a configuration suitable for a particular species ofmammal may be configured so that the zoledronic acid has a 48 hoursustained plasma level factor of about 5 to about 20, about 6 to about15, about 7 or 8 to about 12 or 13, about 8 to about 10, about 11 toabout 13, about 8, about 12, or any 48 hour sustained plasma levelfactor in a range bounded by, or between, any of these values, for theparticular species of mammal.

An oral dosage form comprising zoledronic acid having a dose ofzoledronic acid and a configuration suitable for a particular species ofmammal may be configured so that the zoledronic acid has a 72 hoursustained plasma level factor of about 4 to about 20, about 5 to about10, about 5 or 6 to about 10 or 11, about 5 to about 6, about 9 to about10, about 6, about 10, or any 72 hour sustained plasma level factor in arange bounded by, or between, any of these values, for the particularspecies of mammal.

An oral dosage form comprising zoledronic acid having a dose ofzoledronic acid and a configuration suitable for a particular species ofmammal may be configured so that the particular species of mammal has aplasma concentration of zoledronic acid at 12 hours that is about 0.5ng/mL to about 5 ng/mL, about 1 ng/mL to about 3 ng/mL, about 1 ng/mL toabout 2 ng/mL, about 2 ng/mL to about 3 ng/mL, about 3 ng/mL to about 4ng/mL, about 1.2 ng/mL, about 2.6 ng/mL, about 3.2 ng/mL, or any plasmaconcentration in a range bounded by, or between, any of these values.

An oral dosage form comprising zoledronic acid having a dose ofzoledronic acid and a configuration suitable for a particular species ofmammal may be configured so that the particular species of mammal has aplasma concentration of zoledronic acid at 24 hours that is about 0.2ng/mL to about 2 ng/mL, about 0.5 ng/mL to about 1.5 ng/mL, about 0.5ng/mL to about 1 ng/mL, about 1 ng/mL to about 1.5 ng/mL, about 0.5ng/mL, about 1.0 ng/mL, about 1.4 ng/mL, or any plasma concentration ina range bounded by, or between, any of these values.

An oral dosage form comprising zoledronic acid having a dose ofzoledronic acid and a configuration suitable for a particular species ofmammal may be configured so that the particular species of mammal has aplasma concentration of zoledronic acid at 36 hours that is about 0.1ng/mL to about 2 ng/mL, about 0.2 ng/mL to about 1.5 ng/mL, about 0.2ng/mL to about 0.5 ng/mL, about 0.5 ng/mL to about 1 ng/mL, about 1ng/mL to about 1.3 ng/mL, about 0.3 ng/mL, about 0.8 ng/mL, about 1.1ng/mL, or any plasma concentration in a range bounded by, or between,any of these values.

An oral dosage form comprising zoledronic acid having a dose ofzoledronic acid and a configuration suitable for a particular species ofmammal may be configured so that the particular species of mammal has aplasma concentration of zoledronic acid at 48 hours that is about 0.1ng/mL to about 2 ng/mL, about 0.2 ng/mL to about 1.5 ng/mL, about 0.2ng/mL to about 0.5 ng/mL, about 0.5 ng/mL to about 0.9 ng/mL, about 0.9ng/mL to about 1.3 ng/mL, about 0.3 ng/mL, about 0.7 ng/mL, about 1.1ng/mL, or any plasma concentration in a range bounded by, or between,any of these values.

An oral dosage form comprising zoledronic acid having a dose ofzoledronic acid and a configuration suitable for a particular species ofmammal may be configured so that the particular species of mammal has aplasma concentration of zoledronic acid at 72 hours that is about 0.2ng/mL to about 1 ng/mL, about 0.2 ng/mL to about 1.5 ng/mL, about 0.1ng/mL to about 0.3 ng/mL, about 0.3 ng/mL to about 0.6 ng/mL, about 0.6ng/mL to about 1 ng/mL, about 0.2 ng/mL, about 0.5 ng/mL, about 0.9ng/mL, or any plasma concentration in a range bounded by, or between,any of these values.

An oral dosage form comprising zoledronic acid having a dose ofzoledronic acid and a configuration suitable for a particular species ofmammal may be configured so that the elimination half-life of zoledronicacid in the particular species of mammal is about 30 hours to about 100hours, about 40 hours to about 60 hours, about 40 hours to about 50hours, about 50 hours to about 60 hours, about 42 hours, about 51 hours,about 59 hours, or any half-life in a range bounded by, or between, anyof these values.

As used herein, the “elimination half-life” refers to the apparentfirst-order terminal plasma elimination half-life, obtained bynon-compartmental analysis using Win-Nonlin. A terminal plasmaelimination half-life is the time required to reduce the plasmaconcentration to half after reaching pseudo-equilibrium, and not thetime required to eliminate half the administered dose. For orallyadministered drugs, terminal plasma elimination half-life can beaffected by absorption of the drug, as well as plasma clearance andextent of distribution.

In some embodiments, the disodium salt form of zoledronic acid providesan enhancement to bioavailability, as compared to the diacid form ofzoledronic acid, which adds to any enhancement to bioavailabilityprovided by any bioavailability-enhancing agents in the dosage form. Insome embodiments, the disodium salt form of zoledronic acid provides anenhancement to bioavailability, as compared to the diacid form ofzoledronic acid, which is greater than any enhancement tobioavailability provided by any bioavailability-enhancing agents in thedosage form. In some embodiments, the disodium salt form of zoledronicacid may be administered in a dosage form that is substantially free ofbioavailability-enhancing agents.

In some embodiments, a dosage form comprising a disodium salt ofzoledronic acid is a solid.

In some embodiments, a dosage form comprising a disodium salt ofzoledronic acid is used to treat an inflammatory condition.

In some embodiments, a dosage form comprising a disodium salt ofzoledronic acid is used to treat arthritis.

In some embodiments, a dosage form comprising a disodium salt ofzoledronic acid is used to treat complex regional pain syndrome.

In some embodiments, zoledronic acid is in a form that has an aqueoussolubility, meaning the solubility in water, greater than 1% (w/v),about 5% (w/v) to about 50% (w/v), about 5% (w/v) to about 20% (w/v),about 10% (w/v) to about 15% (w/v), or about 12% (w/v) to about 13%(w/v).

The disodium salt form of zoledronic add can be more compressible thanthe diacid form of zoledronic add. This can make it easier for a dosageform to have a desired hardness. It can also make it easier to increasethe drug load, so that a smaller tablet can be given for a given dosagestrength. In some embodiments, a solid dosage form of zoledronic acid,such as the diacid form of zoledronic acid or the disodium salt form ofzoledronic acid, can have a hardness of about 5 kPa to about 20 kPa orabout 5 kPa to about 14 kPa.

Zoledronic acid or another bisphosphonate may be combined with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice as described, forexample, in Remington's Pharmaceutical Sciences, 2005, the disclosure ofwhich is hereby incorporated herein by reference, in its entirety. Therelative proportions of active ingredient and carrier may be determined,for example, by the solubility and chemical nature of the compounds,chosen route of administration and standard pharmaceutical practice.

Zoledronic acid or another bisphosphonate may be administered by anymeans that may result in the contact of the active agent(s) with thedesired site or site(s) of action in the body of a patient. Thecompounds may be administered by any conventional means available foruse in conjunction with pharmaceuticals, either as individualtherapeutic agents or in a combination of therapeutic agents. Forexample, they may be administered as the sole active agents in apharmaceutical composition, or they can be used in combination withother therapeutically active ingredients.

In some embodiments, an osteoclast inhibitor is co-administered with asteroid. Suitable steroids include, for example, hydrocortisone,hydrocortisone acetate, cortisone acetate, tixocortol pivalate,prednisolone, methylprednisolone, prednisone, triamcinolone acetonide,triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide,fluocinonide, fluocinolone acetonide, halcinonide, betamethasone,betamethasone sodium phosphate, dexamethasone, dexamethasone sodiumphosphate, fluocortolone, hydrocortisone-17-valerate, acleometasonedipropionate, betamethasone valerate, betamethasone dippropionate,prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate,fluocortilone caproate, fluocortolone pivalate, and fluprednideneacetate, hydrocortisone-17-butyrate, 17-aceponate, 17-buteprate, andprednicarbate.

Any effective dose of steroid can be administered to a person. In someembodiment, the dose of a steroid may be about 1 to about 500 mg of thesteroid. In some embodiments, the dose of a steroid does not exceed the25 mg of the steroid, and is not less than 5 mg of the steroid.

The steroid can be given orally (for example, 7.5 mg of prednisone), bya separate infusion (for example, 7.5 mg of methyl prednisolone), mixedin with zoledronic acid in the same infusion, or be administeredintramuscularly, subcutaneously, by rectal suppository, by inhalation,or injected directly into a joint.

Zoledronic acid or another bisphosphonate may be administered to a humanpatient in a variety of forms adapted to the chosen route ofadministration, e.g., orally, rectally, or parenterally. Parenteraladministration in this respect includes, but is not limited to,administration by the following routes: pulmonary, intrathecal,intravenous, intramuscular, subcutaneous, intraocular, intrasynovial,transepithelial including transdermal, sublingual and buccal; topically;nasal inhalation via insufflation; and rectal systemic.

The effective amount of zoledronic acid or another bisphosphonate willvary depending on various factors known to the treating physicians, suchas the severity of the condition to be treated, route of administration,formulation and dosage forms, physical characteristics of thebisphosphonate compound used, and age, weight and response of theindividual patients.

The amount of zoledronic acid or another bisphosphonate in a therapeuticcomposition may vary. For example, some liquid compositions may compriseabout 0.0001% (w/v) to about 50% (w/v), about 0.01% (w/v) to about 20%(w/v), about 0.01% to about 10% (w/v), about 0.001% (w/v) to about 1%(w/v), about 0.1% (w/v) to about 0.5% (w/v), about 1% (w/v) to about 3%(w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) to about 7%(w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15%(w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30%(w/v), about 30% (w/v) to about 40% (w/v), or about 40% (w/v) to about50% (w/v) of zoledronic acid.

Some solid compositions may comprise at least about 5% (w/w), at leastabout 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), atleast about 70% (w/w), at least about 80%, about 10% (w/w) to about 30%(w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30%(w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40%(w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80%(w/w), about 50% (w/w) to about 60% (w/w), about 70% (w/w) to about 75%(w/w), about 70% (w/w) to about 80% (w/w), or about 80% (w/w) to about90% (w/w) of zoledronic acid.

Any suitable amount of an osteoclast inhibitor, including abisphosphonate, such as a nitrogen-containing bisphosphonate, e.g.zoledronic acid, minodronic acid, or ibandronic acid, may be used. Somesolid or liquid oral dosage forms, or units of oral dosage forms(referred to collectively herein as “oral dosage form(s)”) may containabout 0.005 mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.5 mgto about 10 mg, about 0.2 mg to about 5 mg, about 1 mg to about 500 mg,about 1 mg to about 50 mg, about 10 mg to about 250 mg, about 100 mg toabout 300 mg, about 20 mg to about 200 mg, about 20 mg to about 150 mg,about 30 mg to about 100 mg, about 1 mg to about 1,000 mg, about 10 mgto about 50 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg,about 45 mg to about 58 mg, about 45 to about 60 mg, about 50 mg toabout 58 mg, about 50 mg to about 60 mg, about 50 mg to about 55 mg,about 10 mg to about 300 mg, about 10 mg to about 150 mg, about 10 mg toabout 100 mg, about 40 mg to about 150 mg, about 10 mg to about 600 mg,about 40 mg to about 600 mg, about 40 mg to about 2000 mg, about 40 mgto about 800 mg, about 25 mg to about 800 mg, about 30 mg to about 800mg, about 10 mg to about 500 mg, about 50 mg to about 150 mg, about 50mg, about 100 mg, about 50 mg to about 500 mg, about 100 mg to about2000 mg, about 300 mg to about 1500 mg, about 200 mg to about 1000 mg,about 100 mg to about 500 mg, or about 150 mg of zoledronic acid, or anyamount of osteoclast inhibitor in a range bounded by, or between, any ofthese values. In some embodiments, the oral osteoclast inhibitor isadministered daily, weekly, monthly, every two or three months, once ayear, or twice a year.

Some oral dosage forms may contain about 0.005 mg to about 20 mg, about0.1 mg to about 10 mg, about 0.5 mg to about 10 mg, about 0.2 mg toabout 5 mg, about 1 mg to about 500 mg, about 1 mg to about 50 mg, about10 mg to about 250 mg, about 100 mg to about 300 mg, about 20 mg toabout 200 mg, about 20 mg to about 150 mg, about 30 mg to about 100 mg,about 1 mg to about 1,000 mg, about 10 mg to about 50 mg, about 40 mg toabout 60 mg, about 50 mg to about 60 mg, about 55 mg, about 10 mg toabout 300 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg,about 40 mg to about 150 mg, about 10 mg to about 600 mg, about 40 mg toabout 600 mg, about 40 mg to about 2000 mg, about 40 mg to about 800 mg,about 25 mg to about 800 mg, about 30 mg to about 800 mg, about 10 mg toabout 500 mg, about 50 mg to about 150 mg, about 50 mg, about 100 mg,about 50 mg to about 500 mg, about 100 mg to about 2000 mg, about 300 mgto about 1500 mg, about 200 mg to about 1000 mg, about 100 mg to about500 mg, or about 150 mg of osteoclast inhibitor, or any amount ofosteoclast inhibitor in a range bounded by, or between, any of thesevalues. In some embodiments, the oral osteoclast inhibitor isadministered daily, weekly, monthly, every two or three months, once ayear, or twice a year.

In some embodiments, an oral dosage form may contain about 10 mg/m² toabout 20 mg/m², about 15 mg/m² to about 20 mg/m², about 18 mg/m², about80 mg/m² to about 150 mg/m², about 90 mg/m² to about 150 mg/m², about100 mg/m² to about 150 mg/m² of zoledronic acid, or any amount ofzoledronic in a range bounded by, or between, any of these values. Alldosage ranges or amounts expressed in mg/m² are based upon the bodysurface area of the mammal.

In some embodiments, the daily oral dose of an osteoclast inhibitor,including a bisphosphonate, such as a nitrogen-containingbisphosphonate, e.g. zoledronic acid, minodronic acid, or ibandronicacid, is about 0.005 mg to about 20 mg, about 0.1 mg to about 10 mg,about 0.5 mg to about 10 mg, about 0.2 mg to about 5 mg, or any amountin a range bounded by, or between, any of these values. In someembodiments, the daily or dose of osteoclast inhibitor is less thanabout 35 mg/m², less than about 30 mg/m², less than about 25 mg/m²,about 1 mg/m² to about 35 mg/m², about 1 mg/m² to about 30 mg/m², about1.5 mg/m² to about 25 mg/m², about 1.8 mg/m² to about 20 mg/m², about 10mg/m² to about 20 mg/m², about 10 mg/m² to about 30 mg/m², about 15mg/m² to about 20 mg/m², about 18 mg/m², or any amount of zoledronicacid in a range bounded by, or between, any of these values.

In some embodiments, the daily oral dose of an osteoclast inhibitor,including a bisphosphonate, such as a nitrogen-containingbisphosphonate, e.g. zoledronic acid, minodronic acid, or ibandronicacid, is about 0.005 mg to about 20 mg, about 0.1 mg to about 10 mg,about 0.5 mg to about 10 mg, about 0.2 mg to about 5 mg, or any amountof osteoclast inhibitor in a range bounded by, or between, any of thesevalues. In some embodiments, the daily oral dose of osteoclast inhibitoris less than about 35 mg/m², less than about 30 mg/m², less than about25 mg/m², about 1 mg/m² to about 35 mg/m², about 1 mg/m² to about 30mg/m², about 1.5 mg/m² to about 25 mg/m², about 1.8 mg/m² to about 20mg/m², about 10 mg/m² to about 20 mg/m², about 10 mg/m² to about 30mg/m², about 15 mg/m² to about 20 mg/m², about 18 mg/m², or any amountof osteoclast inhibitor in a range bounded by, or between, any of thesevalues.

In some embodiments the daily oral dose of zoledronic add is about 0,005mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.5 mg to about 10mg, about 0.2 mg to about 5 mg, or any amount of zoledronic acid in arange bounded by, or between, any of these values. In some embodiments,the daily oral dose of zoledronic add is less than about 35 mg/m², lessthan about 30 mg/m², less than about 25 mg/m², about 1 mg/m² to about 35mg/m², about 1 mg/m² to about 30 mg/m², about 1.5 mg/m² to about 25mg/m², about 1.8 mg/m² to about 20 mg/m², about 10 mg/m² to about 20mg/m², about 10 mg/m² to about 30 mg/m², about 15 mg/m² to about 20mg/m², about 18 mg/m², or any amount of zoledronic acid in a rangebounded by, or between, any of these values.

In some embodiments, the weekly oral dose of the osteoclast inhibitor,including a bisphosphonate, such as a nitrogen-containingbisphosphonate, e.g. zoledronic acid, minodronic acid, or ibandronicacid, is about 1 mg to about 1000 mg, about 1 mg to about 500 mg, about10 mg to about 250 mg, about 100 mg to about 300 mg, about 10 mg toabout 100 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg,about 10 mg to about 300 mg, about 20 mg to about 150 mg, about 20 mg toabout 60 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg,about 50 mg to about 70 mg, about 50 mg, about 55 mg, about 100 mg toabout 150 mg, or about 30 mg to about 100 mg. In some embodiments, theweekly oral dose of the osteoclast inhibitor is less than about 250mg/m², less than about 200 mg/m², less than about 175 mg/m², about 6mg/m² to about 250 mg/m², about 10 mg/m² to about 210 mg/m², about 10mg/m² to about 170 mg/m², about 4 mg/m² to about 140 mg/m², about 100mg/m² to about 140 mg/m², about 126 mg/m², or any amount in a rangebounded by, or between, any of these values. The weekly oral dose may begiven as a single dose, given once during the week, or may be given in2, 3, 4, 5, 6, or 7 individual doses during the week.

In some embodiments the weekly oral dose of zoledronic acid is about 1mg to about 1000 mg, about 1 mg to about 500 mg, about 10 mg to about250 mg, about 100 mg to about 300 mg, about 10 mg to about 100 mg, about10 mg to about 150 mg, about 10 mg to about 100 mg, about 10 mg to about300 mg, about 20 mg to about 150 mg, about 20 mg to about 60 mg, about30 mg to about 70 mg, about 40 mg to about 60 mg, about 50 ma to about70 mg, about 50 mg to about 55 mg, about 100 mg to about 150 mg, orabout 30 mg to about 100 mg. In some embodiments, the weekly oral doseof zoledronic add is less than about 250 mg/m², less than about 200mg/m², less than about 175 mg/m², about 6 mg/m² to about 250 mg/m²,about 10 mg/m² to about 210 mg/m², about 10 mg/m² to about 170 mg/m²,about 4 mg/m² to about 140 mg/m², about 100 mg/m² to about 140 mg/m²,about 126 mg/m², or any amount of zoledronic acid in a range bounded by,or between, any of these values. The weekly oral dose may be given as asingle dose, given once during the week, or may be given in 2, 3, 4, 5,6, or 7 individual doses during the week.

In some embodiments, the monthly dose of the osteoclast inhibitor,including a bisphosphonate, such as a nitrogen-containingbisphosphonate, e.g. zoledronic acid, minodronic acid, or ibandronicacid, or the amount of the osteoclast inhibitor that is administeredover a period of a month, is about 5000 mg or less, about 4000 mg orless, about 3000 mg or less, about 2000 mg or less, about 1000 mg orless, about 700 mg or less, about 600 mg or less, about 1 mg to about4,000 mg, about 1 ma to about 1.000 mg, about 10 mg to about 1000 mg,about 50 mg to about 1000 mg, about 10 mg to about 600 mg, about 40 mgto about 600 mg, about 50 mg to about 600 mg, about 40 mg to about 400mg, about 50 mg to about 200 mg, about 200 mg to about 300 mg, about 250mg to about 350 mg, or about 100 mg to about 600 mg, about 40 mg toabout 2000 mg, about 40 mg to about 800 mg, about 50 mg to about 800 mg,or about 100 mg to about 800 mg, about 40 mg to about 1000 mg, about 50mg to about 1000 mg, or about 100 mg to about 1000 mg, or any monthlydose in a range bounded by, or between, any of these values. In someembodiments, the monthly oral dose of the osteoclast inhibitor is lessthan about 1000 mg/m², less than about 800 mg/m², less than about 600mg/m², about 10 mg/m² to about 1000 mg/m², about 50 mg/m² to about 800mg/m², about 70 mg/m² to about 700 mg/m², about 100 mg/m² to about 700mg/m², about 100 mg/m² to about 600 mg/m², about 50 mg/m² to about 200mg/m², about 300 mg/m² to about 600 mg/m², about 450 mg/m² to about 600mg/m², about 300 mg/m² to about 1000 mg/m², about 400 mg/m² to about1000 mg/m², about 500 mg/m² to about 1000 mg/m², about 400 mg/m² toabout 700 mg/m², about 500 mg/m² to about 600 mg/m², about 540 mg/m², orany amount in a range bounded by, or between, any of these values. Amonthly dose may be given as a single dose, or as two or more individualdoses administered during the month. In some embodiments, the monthlydose is administered in 2 or 3 weekly doses. In some embodiments, themonthly dose is administered in 4 or 5 weekly doses. In someembodiments, the monthly dose is administered in 28 to 31 daily doses.In some embodiments, the monthly dose is administered in 5 to 10individual doses during the month. The monthly dose may be administeredfor only 1 month, or may be repeatedly administered for 2 or moremonths.

In some embodiments, the monthly dose of zoledronic acid, or the amountof zoledronic acid that is administered over a period of a month, isabout 5000 mg or less, about 4000 mg or less, about 3000 mg or less,about 2000 mg or less, about 1000 mg or less, about 700 mg or less,about 600 mg or less, about 1 mg to about 4,000 mg, about 1 mg to about1,000 mg, about 10 mg to about 1000 mg, about 50 mg to about 1000 mg,about 10 mg to about 600 mg, about 40 mg to about 600 mg, about 50 mg toabout 600 mg, about 40 mg to about 400 mg, about 50 mg to about 200 mg,about 200 mg to about 300 mg, about 250 mg to about 350 mg, or about 100mg to about 600 mg, about 40 mg to about 2000 mg, about 40 mg to about800 mg, about 50 mg to about 800 mg, or about 100 mg to about 800 mg,about 40 mg to about 1000 mg, about 50 mg to about 1000 mg, or about 100mg to about 1000 mg, or any monthly dose in a range bounded by, orbetween, any of these values. In some embodiments, the monthly oral doseof zoledronic acid is less than about 1000 mg/m², less than about 800mg/m², less than about 600 mg/m², about 10 mg/m² to about 1000 mg/m²,about 50 mg/m² to about 800 mg/m², about 70 mg/m² to about 700 mg/m²,about 100 mg/m² to about 700 mg/m², about 100 mg/m² to about 600 mg/m²,about 50 mg/m² to about 200 mg/m², about 300 mg/m² to about 600 mg/m²,about 450 mg/m² to about 600 mg/m², about 300 mg/m² to about 1000 mg/m²,about 400 mg/m² to about 1000 mg/m², about 500 mg/m² to about 1000mg/m², about 400 mg/m² to about 700 mg/m², about 500 mg/m² to about 600mg/m², about 540 mg/m², or any amount of zoledronic acid in a rangebounded by, or between, any of these values. A monthly dose may be givenas a single dose, or as two or more individual doses administered duringthe month. In some embodiments, the monthly dose is administered in 2 or3 weekly doses. In some embodiments, the monthly dose is administered in4 or 5 weekly doses. In some embodiments, the monthly dose isadministered in 28 to 31 daily doses. In some embodiments, the monthlydose is administered in 5 to 10 individual doses during the month. Themonthly dose may be administered for only 1 month, or may be repeatedlyadministered for 2 or more months.

With respect to orally administering zoledronic acid to a mammal, suchas a dog, a rat, a rabbit, a monkey, an ape, or a human being, doses ofabout 0.03 mg/kg to about 10 mg/kg, or any smaller range within thisrange, such as about 0.4 mg/kg to about 3 mg/kg, about 0.4 mg/kg toabout 1.5 mg/kg, mg/kg, about 0.4 mg/kg to about 0.5 mg/kg, about 0.5mg/kg to about 0.6 mg/kg, about 0.6 mg/kg to about 0.7 mg/kg, about 0.7mg/kg to about 0.8 mg/kg, about 0.8 mg/kg to about 0.9 mg/kg, about 0.9mg/kg to about 1 mg/kg, about 1 mg/kg to about 1.1 mg/kg, about 1.1mg/kg to about 1.2 mg/kg, about 1.2 mg/kg to about 1.3 mg/kg, about 1.3mg/kg to about 1.4 mg/kg, about 1.4 mg/kg to about 1.5 mg/kg, about 1.5mg/kg to about 1.6 mg/kg, about 1.6 mg/kg to about 1.7 mg/kg, about 1.7mg/kg to about 1.8 mg/kg, about 1.8 mg/kg to about 1.9 mg/kg, about 1.9mg/kg to about 2 mg/kg, about 2 mg/kg to about 2.1 mg/kg, about 2.1mg/kg to about 2.2 mg/kg, about 2.2 mg/kg to about 2.3 mg/kg, about 2.3mg/kg to about 2.4 mg/kg, about 2.4 mg/kg to about 2.5 mg/kg, about 2.5mg/kg to about 2.6 mg/kg, about 2.6 mg/kg to about 2.7 mg/kg, about 2.7mg/kg to about 2.8 mg/kg, about 2.8 mg/kg to about 2.9 mg/kg, about 2.9mg/kg to about 3 mg/kg, about 3 mg/kg to about 3.1 mg/kg, about 3.1mg/kg to about 3.2 mg/kg, about 3.2 mg/kg to about 3.3 mg/kg, about 3.3mg/kg to about 3.4 mg/kg, about 3.4 mg/kg to about 3.5 mg/kg, about 3.5mg/kg to about 3.6 mg/kg, about 3.6 mg/kg to about 3.7 mg/kg, about 3.7mg/kg to about 3.8 mg/kg, about 3.8 mg/kg to about 3.9 mg/kg, about 3.9mg/kg to about 4 mg/kg, about 0.4 mg/kg to about 0.6 mg/kg, about 0.6mg/kg to about 0.8 mg/kg, about 0.8 mg/kg to about 1 mg/kg, about 1mg/kg to about 1.2 mg/kg, about 1.2 mg/kg to about 1.4 mg/kg, about 1.4mg/kg to about 1.6 mg/kg, about 1.6 mg/kg to about 1.8 mg/kg, about 1.8mg/kg to about 2 mg/kg, about 2 mg/kg to about 2.2 mg/kg, about 2.2mg/kg to about 2.4 mg/kg, about 2.4 mg/kg to about 2.6 mg/kg, about 2.6mg/kg to about 2.8 mg/kg, about 2.8 mg/kg to about 3 mg/kg, about 3mg/kg to about 3.2 mg/kg, about 3.2 mg/kg to about 3.4 mg/kg, about 3.4mg/kg to about 3.6 mg/kg, about 3.6 mg/kg to about 3.8 mg/kg, about 3.8mg/kg to about 4 mg/kg, about 0.4 mg/kg to about 0.7 mg/kg, about 0.7mg/kg to about 1 mg/kg, about 1 mg/kg to about 1.3 mg/kg, about 1.3mg/kg to about 1.6 mg/kg, about 1.6 mg/kg to about 1.9 mg/kg, about 1.9mg/kg to about 2.2 mg/kg, about 2.2 mg/kg to about 2.5 mg/kg, about 2.5mg/kg to about 2.8 mg/kg, about 2.8 mg/kg to about 3 mg/kg, about 3.3mg/kg to about 3.6 mg/kg, about 3.6 mg/kg to about 4 mg/kg, about 0.4mg/kg to about 1 mg/kg, or about 0.5 mg/kg to about 1 mg/kg, may be asafe dose for repeated oral administration, such as once daily dosing toonce yearly dosing, once daily dosing to twice yearly dosing, once dailydosing to thrice yearly dosing, once daily dosing to dosing every threemonths, once daily dosing to dosing every two months, once daily dosingto dosing every two months, once daily dosing to dosing every month,once daily dosing to dosing every 2-4 weeks, once daily dosing to onceweekly dosing, etc.

The doses referred to in the paragraph above for administration ofzoledronic acid to a mammal may be safely administered 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 times, or about 3 to about 10 times,once a day, or less frequently, such as once week, once every two weeks,once a month, etc.

For once daily to once weekly oral administration of zoledronic acid toa mammal such as a mouse, rat, dog, primate, or a human being, in someembodiments, a safely repeated dose may be about 0.03 mg/kg to about 4mg/kg, or any smaller range within this range, such as about 0.01 mg/kgto about 0.02 mg/kg, about 0.02 mg/kg to about 0.03 mg/kg, about 0.03mg/kg to about 0.04 mg/kg, about 0.04 mg/kg to about 0.05 mg/kg, about0.05 mg/kg to about 0.06 mg/kg, about 0.06 mg/kg to about 0.07 mg/kg,about 0.07 mg/kg to about 0.08 mg/kg, about 0.08 mg/kg to about 0.09mg/kg, about 0.09 mg/kg to about 0.1 mg/kg, about 0.1 mg/kg to about0.11 mg/kg, about 0.11 mg/kg to about 0.12 mg/kg, about 0.12 mg/kg toabout 0.13 mg/kg, about 0.13 mg/kg to about 0.14 mg/kg, about 0.14 mg/kgto about 0.15 mg/kg, about 0.15 mg/kg to about 0.16 mg/kg, about 0.16mg/kg to about 0.17 mg/kg, about 0.17 mg/kg to about 0.18 mg/kg, about0.18 mg/kg to about 0.19 mg/kg, about 0.19 mg/kg to about 0.2 mg/kg,about 0.2 mg/kg to about 0.21 mg/kg, about 0.21 mg/kg to about 0.22mg/kg, about 0.22 mg/kg to about 0.23 mg/kg, about 0.23 mg/kg to about0.24 mg/kg, about 0.24 mg/kg to about 0.25 mg/kg, about 0.25 mg/kg toabout 0.26 mg/kg, about 0.26 mg/kg to about 0.27 mg/kg, about 0.27 mg/kgto about 0.28 mg/kg, about 0.28 mg/kg to about 0.29 mg/kg, about 0.29mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.31 mg/kg, about0.31 mg/kg to about 0.32 mg/kg, about 0.32 mg/kg to about 0.33 mg/kg,about 0.33 mg/kg to about 0.34 mg/kg, about 0.34 mg/kg to about 0.35mg/kg, about 0.35 mg/kg to about 0.36 mg/kg, about 0.36 mg/kg to about0.37 mg/kg, about 0.37 mg/kg to about 0.38 mg/kg, about 0.38 mg/kg toabout 0.39 mg/kg, about 0.39 mg/kg to about 0.4 mg/kg, about 0.05 mg/kgto about 0.2 mg/kg, about 0.05 mg/kg to about 0.15 mg/kg, about 0.06mg/kg to about 0.15 mg/kg, about 0.07 mg/kg to about 0.15 mg/kg, about0.08 mg/kg to about 0.15 mg/kg, about 0.09 mg/kg to about 0.15 mg/kg,about 0.1 mg/kg to about 0.15 mg/kg, about 0.03 mg/kg to about 0.5mg/kg, about 0.06 mg/kg to about 0.2 mg/kg, about 0.07 mg/kg to about0.2 mg/kg, about 0.08 mg/kg to about 0.2 mg/kg, about 0.09 mg/kg toabout 0.2 mg/kg, about 0.1 mg/kg to about 0.2 mg/kg, about 0.4 mg toabout 4 mg, about 0.4 mg/kg to about 0.6 mg/kg, about 0.6 mg/kg to about0.8 mg/kg, about 0.8 mg/kg to about 1 mg/kg, about 1 mg/kg to about 1.2mg/kg, about 1.2 mg/kg to about 1.4 mg/kg, about 1.4 mg/kg to about 1.6mg/kg, about 1.6 mg/kg to about 1.8 mg/kg, about 1.8 mg/kg to about 2mg/kg, about 2 mg/kg to about 2.2 mg/kg, about 2.2 mg/kg to about 2.4mg/kg, about 2.4 mg/kg to about 2.6 mg/kg, about 2.6 mg/kg to about 2.8mg/kg, about 2.8 mg/kg to about 3 mg/kg, about 3 mg/kg to about 3.2mg/kg, about 3.2 mg/kg to about 3.4 mg/kg, about 3.4 mg/kg to about 3.6mg/kg, about 3.6 mg/kg to about 3.8 mg/kg, about 3.8 mg/kg to about 4mg/kg, about 0.5 mg/kg to about 2 mg/kg, about 0.6 mg/kg to about 2mg/kg, about 0.7 mg/kg to about 2 mg/kg, about 0.8 mg/kg to about 2mg/kg, about 0.5 mg/kg to about 1.5 mg/kg, about 0.6 mg/kg to about 1.5mg/kg, about 0.7 mg/kg to about 1.5 mg/kg, about 0.8 mg/kg to about 1.5mg/kg, about 0.5 mg/kg to about 0.9 mg/kg, about 0.6 mg/kg to about 0.9mg/kg, about 0.7 mg/kg to about 0.9 mg/kg, about 0.5 mg/kg to about 1mg/kg, about 0.6 mg/kg to about 1 mg/kg, about 0.7 mg/kg to about 1mg/kg, about 0.8 mg/kg to about 1 mg/kg, or about 0.8 mg/kg to about 0.9mg/kg.

For once weekly or less frequent oral administration, such as every 2weeks or every other week, of zoledronic acid to a mammal such as amouse, rat, dog, primate, or a human being, in some embodiments, asafely repeated dose may be about 0.4 mg to about 10 mg, or any smallerrange within this range, such as about 0.4 mg/kg to about 0.6 mg/kg,about 0.6 mg/kg to about 0.8 mg/kg, about 0.8 mg/kg to about 1 mg/kg,about 1 mg/kg to about 1.2 mg/kg, about 1.2 mg/kg to about 1.4 mg/kg,about 1.4 mg/kg to about 1.6 mg/kg, about 1.6 mg/kg to about 1.8 mg/kg,about 1.8 mg/kg to about 2 mg/kg, about 2 mg/kg to about 2.2 mg/kg,about 2.2 mg/kg to about 2.4 mg/kg, about 2.4 mg/kg to about 2.6 mg/kg,about 2.6 mg/kg to about 2.8 mg/kg, about 2.8 mg/kg to about 3 mg/kg,about 3 mg/kg to about 3.2 mg/kg, about 3.2 mg/kg to about 3.4 mg/kg,about 3.4 mg/kg to about 3.6 mg/kg, about 3.6 mg/kg to about 3.8 mg/kg,about 3.8 mg/kg to about 4 mg/kg, about 4 mg/kg to about 4.2 mg/kg,about 4.2 mg/kg to about 4.4 mg/kg, about 4.4 mg/kg to about 4.6 mg/kg,about 4.6 mg/kg to about 4.8 mg/kg, about 4.8 mg/kg to about 5 mg/kg,about 5 mg/kg to about 5.2 mg/kg, about 5.2 mg/kg to about 5.4 mg/kg,about 5.4 mg/kg to about 5.6 mg/kg, about 5.6 mg/kg to about 5.8 mg/kg,about 5.8 mg/kg to about 6 mg/kg, about 6 mg/kg to about 6.2 mg/kg,about 6.2 mg/kg to about 6.4 mg/kg, about 6.4 mg/kg to about 6.6 mg/kg,about 6.6 mg/kg to about 6.8 mg/kg, about 6.8 mg/kg to about 7 mg/kg,about 7 mg/kg to about 7.2 mg/kg, about 7.2 mg/kg to about 7.4 mg/kg,about 7.4 mg/kg to about 7.6 mg/kg, about 7.6 mg/kg to about 7.8 mg/kg,about 7.8 mg/kg to about 8 mg/kg, about 8 mg/kg to about 8.2 mg/kg,about 8.2 mg/kg to about 8.4 mg/kg, about 8.4 mg/kg to about 8.6 mg/kg,about 8.6 mg/kg to about 8.8 mg/kg, about 8.8 mg/kg to about 9 mg/kg,about 9 mg/kg to about 9.2 mg/kg, about 9.2 mg/kg to about 9.4 mg/kg,about 9.4 mg/kg to about 9.6 mg/kg, about 9.6 mg/kg to about 9.8 mg/kg,about 9.8 mg/kg to about 10 mg/kg, about 0.5 mg/kg to about 2 mg/kg,about 0.6 mg/kg to about 2 mg/kg, about 0.7 mg/kg to about 2 mg/kg,about 0.8 mg/kg to about 2 mg/kg, about 0.5 mg/kg to about 1.5 mg/kg,about 0.6 mg/kg to about 1.5 mg/kg, about 0.7 mg/kg to about 1.5 mg/kg,about 0.8 mg/kg to about 1.5 mg/kg, about 0.5 mg/kg to about 1 mg/kg,about 0.6 mg/kg to about 1 mg/kg, about 0.7 mg/kg to about 1 mg/kg,about 0.8 mg/kg to about 1 mg/kg, or about 0.8 mg/kg to about 0.9 mg/kg,

In some embodiments, the osteoclast inhibitor comprises zoledronic acid,and the oral zoledronic acid, or disodium salt thereof, may beadministered in combination with about 0.1 mg to about 10 mg ofzoledronic acid, or a salt thereof, administered parenterally, such asintravenously. In some embodiments, about 50 mg, about 100 mg, or about150 mg of the disodium salt of zoledronic acid is administered orally incombination with 1 mg parenteral, such as intravenous, zoledronic acid.In some embodiments the parenteral dose of zoledronic acid is about 0.25mg to about 25 mg, about 0.25 mg to about 10 mg, or about 0.5 mg toabout 7.5 mg.

With respect to oral administration of an osteoclast inhibitor, such aszoledronic acid, minodronic acid, ibandronic acid, or anotherbisphosphonate, for the treatment of pain associated with inflammation,arthritis, CRPS, or any other condition recited herein, it may helpfulif the mammal or human being to which the osteoclast inhibitor isadministered does not eat food or drink beverage, (other than any waterrequired to swallow the oral dosage form) for at least about 1 hour, atleast about 2 hours, at least about 4 hours, at least about 6 hours, atleast about 8 hours, at least about 10 hours, or at least about 12 hoursbefore the osteoclast inhibitor is administered. It may also be helpfulif the mammal or human being to which the osteoclast inhibitor isadministered does not eat food or drink beverage for at least about 30minutes, at least about 1 hour, at least about 2 hours, at least about 3hours, or at least about 4 hours after the osteoclast inhibitor isadministered. In some embodiments, a human being to which the zoledronicacid is administered avoids lying down, or remains upright or sitsupright, for at least about 30 minutes or about 1 hour after receiving adosage form containing the osteoclast inhibitor. Avoiding food orbeverage before or after oral administration of the osteoclast inhibitorcan improve the bioavailability of the osteoclast inhibitor.

The oral bioavailability of osteoclast inhibitor in a dosage form canvary. Some dosage forms may have ingredients added to enhance thebioavailability. However, bioavailability enhancement is not necessaryfor an oral dosage form to be effective. In some embodiments, the dosageform is substantially free of bioavailability-enhancing agents. In someembodiments, an oral dosage form may have an oral bioavailability of theosteoclast inhibitor—such as zoledronic acid, minodronic acid,ibandronic acid—of about 0.01% to about 10%, about 0.1% to about 7%,about 0.1% to about 5%, etc. Without ingredients or other methods toenhance bioavailability, bisphosphonates such as zoledronic acidtypically have a low bioavailability in an oral dosage form. In someembodiments, the oral bioavailability of zoledronic acid is unenhancedor substantially unenhanced. For example, the oral bioavailability ofzoledronic acid can be about 0.01% to about 5%, about 0.01% to about 4%,about 0.1% to about 3%, about 0.1% to about 2%, about 0.2% to about 2%,about 0.2% to about 1.5%, about 0.3% to about 1.5%, about 0.3% to about1%, about 1% to about 3%, about 1.2% to about 3.5%, about 1.2% to about3%, about 1% to about 4%, about 1.5% to about 4.5%, about 0.1% to about0.5%, about 0.3% to about 0.5%, about 0.5% to about 1%, about 0.6% toabout 0.7%, about 0.7% to about 0.8%, about 0.8% to about 0.9%, about0.9%, about 1% to about 1.1%, about 1.1% to about 1.2%, about 1.2% toabout 1.3%, about 1.3% to about 1.4%, about 1.4% to about 1.5%, about1.5% to about 1.6%, about 1.6% to about 1.8%, about 1.8% to about 2%, orabout 2% to 2.5%.

One embodiment is a pharmaceutical composition comprising an osteoclastinhibitor such as zoledronic add, minodronic acid, or ibandronic acidwherein the oral bioavailability of zoledronic acid in the dosage formis from about 0.01% to about 10%.

In some embodiments, the oral bioavailability of the osteoclastinhibitor in the dosage form is about 0.01% to about 5%, about 0.1% toabout 7%, about 0.1% to about 5%, about 0.1% to about 3%, about 0.1% toabout 2%, about 0.2% to about 2%, about 0.2% to about 1.5%, about 0.3%to about 1.5%, or about 0.3% to about 1.0%.

In some embodiments, the oral bioavailability of zoledronic acid in thedosage form is about 0.01% to about 5%.

In some embodiments, the oral bioavailability of zoledronic acid in thedosage form is about 0.1% to about 7%.

In some embodiments, the oral bioavailability of zoledronic acid in thedosage form is about 0.1% to about 5%.

In some embodiments, the oral bioavailability of zoledronic acid in thedosage form is about 0.1% to about 3%.

In some embodiments, the oral bioavailability of zoledronic acid in thedosage form is about 0.1% to about 2%.

In some embodiments, the oral bioavailability of zoledronic acid in thedosage form is about 0.2% to about 2%.

In some embodiments, the oral bioavailability of zoledronic acid in thedosage form is about 0.2% to about 1.5%.

In some embodiments, the oral bioavailability of zoledronic acid in thedosage form is about 0.3% to about 1.5%.

In some embodiments, the oral bioavailability of zoledronic acid in thedosage form is about 0.3% to about 1.0%.

In some embodiments, an oral dosage form comprises about 10 mg to about300 mg of zoledronic acid, minodronic acid, or ibandronic acid and isadministered daily for about 2 to about 15 consecutive days. Thisregimen may be repeated once monthly, once every two months, once everythree months, once every four months, once every five months, once everysix months, once yearly, or once every two years.

In some embodiments, an oral dosage form comprises about 10 mg to about150 mg or about 10 mg to about 100 mg of zoledronic acid, minodronicacid, or ibandronic acid and is administered daily for about 2 to about15 consecutive days. This regimen may be repeated once monthly, onceevery two months, once every three months, once every four months, onceevery five months, once every six months, once yearly, or once every twoyears.

In some embodiments, an oral dosage form comprises about 10 mg to about150 mg or about 10 mg to about 100 mg of zoledronic acid, minodronicacid, or ibandronic acid and is administered daily for about 5 to about10 consecutive days. This regimen may be repeated once monthly, onceevery two months, once every three months, once every four months, onceevery five months, once every six months, once yearly, or once every twoyears.

In some embodiments, an oral dosage form comprises about 40 mg to about150 mg of zoledronic acid, minodronic acid, or ibandronic acid and isadministered daily for about 5 to about 10 consecutive days. Thisregimen may be repeated once monthly, once every two months, once everythree months, once every four months, once every five months, once everysix months, once yearly, or once every two years.

In some embodiments, the oral zoledronic acid, minodronic acid, oribandronic acid may be administered as one dose of about 100 mg to about2000 mg. In some embodiments, the oral zoledronic acid, minodronic acid,or ibandronic acid may be administered as one dose of about 300 mg toabout 1500 mg. In some embodiments, the oral zoledronic acid, minodronicacid, or ibandronic acid may be administered as one dose of about 200 mgto about 1000 mg. The dose of zoledronic acid, minodronic acid, oribandronic acid may be administered in a single or divided dose.

An osteoclast inhibitor, such as zoledronic acid, minodronic acid, oribandronic acid, may be formulated for oral administration, for example,with an inert diluent or with an edible carrier, or it may be enclosedin hard or soft shell gelatin capsules, compressed into tablets, orincorporated directly with the food of the diet. For oral therapeuticadministration, the active compound may be incorporated with anexcipient and used in the form of ingestible tablets, buccal tablets,coated tablets, troches, capsules, elixirs, dispersions, suspensions,solutions, syrups, wafers, patches, and the like.

Tablets, troches, pills, capsules and the like may also contain one ormore of the following: a binder such as gum tragacanth, acacia, cornstarch or gelatin; an excipient, such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; a sweetening agentsuch as sucrose, lactose or saccharin; or a flavoring agent such aspeppermint, oil of wintergreen or cherry flavoring. When the unit dosageform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier. Various other materials may be present ascoating, for instance, tablets, pills, or capsules may be coated withshellac, sugar or both. A syrup or elixir may contain the activecompound, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring, such as cherry or orange flavor. Itmay be desirable for material in a dosage form or pharmaceuticalcomposition to be pharmaceutically pure and substantially non toxic inthe amounts employed.

Some compositions or dosage forms may be a liquid, or may comprise asolid phase dispersed in a liquid.

An osteoclast inhibitor, such as zoledronic acid, minodronic acid, oribandronic acid may be formulated for parental or intraperitonealadministration. Solutions of the active compounds as free acids orpharmacologically acceptable salts can be prepared in water suitablymixed with a surfactant, such as hydroxypropylcellulose. A dispersioncan also have an oil dispersed within, or dispersed in, glycerol, liquidpolyethylene glycols, and mixtures thereof. Under ordinary conditions ofstorage and use, these preparations may contain a preservative toprevent the growth of microorganisms.

In some embodiments, an oral dosage form may comprise a silicifiedmicrocrystalline cellulose such as Prosolv. For example, about 20%(wt/wt) to about 70% (wt/wt), about 10% (wt/wt) to about 20% (wt/wt),about 20% (wt/wt) to about 40% (wt/wt), about 25% (wt/wt) to about 30%(wt/wt), about 40% (wt/wt) to about 50% (wt/wt), or about 45% (wt/wt) toabout 50% (wt/wt) silicified microcrystalline cellulose may be presentin an oral dosage form or a unit of an oral dosage form.

In some embodiments, an oral dosage form may comprise a crosslinkedpolyvinylpyrrolidone such as crospovidone. For example, about 1% (wt/wt)to about 10% (wt/wt), about 1% (wt/wt) to about 5% (wt/wt), or about 1%(wt/wt) to about 3% (wt/wt) crosslinked polyvinylpyrrolidone may bepresent in an oral dosage form or a unit of an oral dosage form.

In some embodiments, an oral dosage form may comprise a fumed silicasuch as Aerosil. For example, about 0.1% (wt/wt) to about 10% (wt/wt),about 0.1% (wt/wt) to about 1% (wt/wt), or about 0.4% (wt/wt) to about0.6% (wt/wt) fumed silica may be present in an oral dosage form or aunit of an oral dosage form.

In some embodiments, an oral dosage form may comprise magnesiumstearate. For example, about 0.1% (wt/wt) to about 10% (wt/wt), about0.1% (wt/wt) to about 1% (wt/wt), or about 0.4% (wt/wt) to about 0.6%(wt/wt) magnesium stearate may be present in an oral dosage form or aunit of an oral dosage form.

An oral dosage form comprising zoledronic acid or another bisphosphonateor osteoclast inhibitor may be included in a pharmaceutical productcomprising more than one unit of the oral dosage form.

A pharmaceutical product containing oral dosage forms for daily use cancontain 28, 29, 30, or 31 units of the oral dosage form for a monthlysupply. An approximately 6 week daily supply can contain 40 to 45 unitsof the oral dosage form. An approximately 3 month daily supply cancontain 85 to 95 units of the oral dosage form. An approximatelysix-month daily supply can contain 170 to 200 units of the oral dosageform. An approximately one year daily supply can contain 350 to 380units of the oral dosage form.

A pharmaceutical product containing oral dosage forms for weekly use cancontain 4 or 5 units of the oral dosage form for a monthly supply. Anapproximately 2 month weekly supply can contain 8 or 9 units of the oraldosage form. An approximately 6 week weekly supply can contain about 6units of the oral dosage form. An approximately 3 month weekly supplycan contain 12, 13 or 14 units of the oral dosage form. An approximatelysix-month weekly supply can contain 22 to 30 units of the oral dosageform. An approximately one year weekly supply can contain 45 to 60 unitsof the oral dosage form.

A pharmaceutical product may accommodate other dosing regimes. Forexample, a pharmaceutical product may comprise 5 to 10 units of the oraldosage form, wherein each unit of the oral dosage form contains about 40mg to about 150 mg of zoledronic acid, minodronic acid, or ibandronicacid. Some pharmaceutical products may comprise 1 to 10 units of theoral dosage form, wherein the product contains about 200 mg to about2000 mg of zoledronic acid, minodronic acid, or ibandronic acid. Forsuch a product, each unit of the oral dosage form may be taken daily for1 to 10 days or 5 to 10 days during a month, such as at the beginning ofa month.

Some oral dosage forms comprising an osteoclast inhibitor—such assuitable bisphosphonates like zoledronic acid, minodronic acid, oribandronic acid or salts thereof—may have enteric coatings or filmcoatings. In some embodiments, an oral dosage form of an osteoclastinhibitor comprises a tablet having an enteric coating. In someembodiments, an oral dosage form of an osteoclast inhibitor comprises acapsule having an enteric coating. In some embodiments, an oral dosageform of an osteoclast inhibitor comprises a tablet having a filmcoating. In some embodiments, an oral dosage form of an osteoclastinhibitor comprises a capsule having a film coating.

Useful doses for an antibody against RANK or RANKL, such as denosumab,may range from about 0.1 mg/kg to about 20 mg/kg, about 0.75 mg/kg toabout 7.5 mg/kg, about 0.1 mg/kg to about 5 mg/kg, about 1 mg/kg toabout 2 mg/kg, about 10 mg/kg to about 20 mg/kg, about 12 to about 17mg/kg, about 15 mg/kg to about 20 mg/kg, about 1 mg/kg, about 1 mg/kg toabout 10 mg/kg, or any value bounded by or in between these ranges basedon the body weight of the mammal. The chosen dose may be administeredrepeatedly, particularly for chronic conditions, or the amount per dosemay be increased or decreased as treatment progresses. The chosen dosemay be administered one or more times per week, monthly, every twomonths, every three months, every six months, or every year.

In some embodiments, 60 mg of denosumab is administered subcutaneouslyto patient in need of treatment. In some embodiments, the administrationis repeated every six months.

There are a number of ways that some part of Compound 1 and/or Compound2 may be removed from a zoledronic acid product. For example, HPLC,preparative TLC, crystallization, sublimation, or zone purification maybe employed. Solvents that may be useful in HPLC, TLC, orcrystallization, may include, but are not limited to, water or organicsolvents, such as hexanes, diethyl ether, ethyl acetate, methyl acetate,acetone, acetic acid, acetonitrile, tetrahydrofuran, ethanol, methanol,isopropyl alcohol, chloroform, diethyl ether, toluene,dimethylformamide, benzene, etc. Gradients, or two solvent systems maybe employed as well. For example, an HPLC separation may begin byelution with water, after some time eluting with water, an organicsolvent, such as acetonitrile, methanol, ethanol, ethyl acetate,acetone, acetic acid, methyl acetate, or another solvent could graduallybe added to the water, or may replace the water entirely. Similarly,crystallization or recrystallization may employ a single solvent, or acombination of solvents. For example, zoledronic acid or a salt thereof,such as a disodium salt, might be recrystallized from water, ethanol,methanol, diethyl ether, methyl acetate, acetic acid, etc., or acombination of these solvents or others. In some embodiments, zoledronicacid or a salt thereof, such as a disodium salt, may be dissolved in onesolvent, such as water or acetic acid, and crystallized by a secondsolvent or solvent system, such as hexane, diethyl ether, chloroform,dichloromethane, ethyl acetate, methyl acetate, acetic acid, ethanol,methanol, or a combination thereof. In some embodiments, a disodium saltof zoledronic acid is dissolved in water, and then crystallized byadding hexane. In some embodiments, a disodium salt of zoledronic acidis dissolved in water, and then crystallized by adding diethyl ether. Insome embodiments, a disodium salt of zoledronic acid is dissolved inwater, and then crystallized by adding chloroform. In some embodiments,a disodium salt of zoledronic acid is dissolved in water, and thencrystallized by adding dichloromethane. In some embodiments, a disodiumsalt of zoledronic acid is dissolved in water, and then crystallized byadding ethyl acetate. In some embodiments, a disodium salt of zoledronicacid is dissolved in water, and then crystallized by adding methylacetate. In some embodiments, a disodium salt of zoledronic acid isdissolved in water, and then crystallized by adding acetic acid. In someembodiments, a disodium salt of zoledronic acid is dissolved in water,and then crystallized by adding ethanol. In some embodiments, a disodiumsalt of zoledronic acid is dissolved in water, and then crystallized byadding methanol. For embodiments employing water and a second solvent,the ratio of water to the second solvent (water:second solvent) may beabout 1:100 to about 100:1, about 1:10 to about 1:5, about 1:5 to about1:4, about 1:4 to about 1:3, about 1:3 to about 1:2, about 1:2 to about1:1, about 1:1 to about 2:1, about 2:1 to about 3:1, about 3:1 to about4:1, about 4:1 to about 5:1, or about 1:1 to about 10:1.

In some embodiments, a combination of two methods recited in theparagraph above may be employed, such as HPLC or TLC andcrystallization. In some embodiments, a method may be repeated, such asHPLC, preparative TLC, crystallization, sublimation, or zonepurification. In some embodiments, a purification method recited in theparagraph above may be performed twice. In some embodiments, apurification method recited in the paragraph above may be performedthree or four times.

In the examples below, zoledronic acid was administered in the disodiumsalt form as disodium zoledronate tetrahydrate. No bioavailabilityenhancing agents were used in the test compositions.

Example 1 Effect of Orally Administered Zoledronic Acid in Rat Model ofInflammatory Pain Method

The effect of orally administered zoledronic acid on inflammatory painwas examined using the rat complete Freund's adjuvant (CFA) model.Inflammatory pain was induced by injection of 100% CFA in a 75 μL volumeinto the left hind paws of Sprague-Dawley rats on day 0, followed byassessments on days 1-3. Animals were orally administered vehicle(control), zoledronic acid 18 mg/m² (or 3 mg/kg), zoledronic acid 120mg/m² (or 20 mg/kg), or zoledronic acid 900 mg/m² (or 150 mg/kg) dailyon days 1-3. Drug was dissolved in distilled water and prepared freshdaily. Animals were fasted prior to dosing. Under current FDA guidelinesfor extrapolating starting dosages from animals to humans, dosagesexpressed in mg/m² are considered equivalent between mammalian species.Thus, for example, 18 mg/m² in a rat is considered equivalent to 18mg/m² in a human being, while 3 mg/kg in a rat may not be equivalent to3 mg/kg in a human being.

Values for inflammatory pain (mechanical hyperalgesia) in the vehicleand drug-treated animals were obtained on day 0 prior to CFA injection,and at baseline and post-treatment on days 1-3. Pain was assessed usinga digital Randall-Selitto device (dRS; IITC Life Sciences, WoodlandHills, Calif.). Animals were placed in a restraint sling that suspendedthe animal, leaving the hind limbs available for testing. Pawcompression threshold was measured by applying increasing pressure tothe plantar surface of the hind paw with a dome-shaped tip placedbetween the 3rd and 4th metatarsus. Pressure was applied gradually overapproximately 10 seconds. Measurements were taken from the firstobserved nocifensive behavior of vocalization, struggle or withdrawal. Acut-off value of 300 g was used to prevent injury to the animal.

Reversal of inflammatory pain was calculated according to the formula:

% reversal=(Post-treatment−Post-CFA baseline)/(Pre-CFA baseline−Post-CFAbaseline)×100.

The experiment was carried out using 9-10 animals per group.

Results:

Oral administration of zoledronic acid significantly improvedinflammatory pain thresholds compared to vehicle. Pain thresholdmeasurements taken at various times are shown in FIG. 1. Paw compressionthresholds in the 18 mg/m² group were higher than for vehicle during theentire measurement period after 30 minutes from the start of treatment.On day three, paw compression thresholds for both the 18 mg/m² and 900mg/m² groups were greater than for vehicle. An improvement in painthreshold of 49% and 83% from baseline was observed for the 18 mg/m² andthe 900 mg/m² groups respectively.

Orally administered zoledronic acid produced a 29% reversal ofinflammatory pain at the 18 mg/m², and a 48% reversal at the 900 mg/m²dose. This magnitude of effect is comparable to that obtained withclinical doses of commercially available NSAIDs when tested in a similarmodel of inflammatory pain. Under current FDA guidelines, the referencebody surface area of a human adult is 1.62 m². Thus, a daily dose of 18mg/m² corresponds to a monthly dose of about 500-560 mg/m² or a humandose of about 800-900 mg.

Surprisingly, the two higher doses resulted in thresholds that werelower than vehicle on the first two days of dosing. The 120 mg/m² groupwas approximately equal or inferior to vehicle at all time points duringthe assessment period. While the 900 mg/m² group showed effectiveness onday 3, this result was accompanied by significant toxicity necessitatingeuthanization of all the animals in this group two days after cessationof dosing.

Example 2 Effect of Orally Administered Zoledronic Acid in Rat Model ofArthritis Pain Method

The effect of orally administered zoledronic acid on arthritis pain wasexamined in the rat complete Freund's adjuvant (CFA) model of arthritispain. In this model, injection of 100% complete Freund's adjuvant (CFA)in a 75 μL volume into the left hind paws is followed by a 10-14 dayperiod to allow for the development of arthritis pain. Animals wereorally administered vehicle (control), zoledronic acid 54 mg/m² (or 9mg/kg), or zoledronic acid 360 mg/m² (or 60 mg/kg), divided in threeequal daily doses on the first three days post CFA injection. Drug wasdissolved in distilled water and prepared fresh daily. Animals werefasted prior to dosing.

Arthritis pain (mechanical hyperalgesia) in the vehicle and drug-treatedanimals was evaluated on day 14 post CFA injection using a digitalRandall-Selitto device (dRS; IITC Life Sciences, Woodland Hills,Calif.). Animals were placed in a restraint sling that suspended theanimal, leaving the hind limbs available for testing. Paw compressionthreshold was measured by applying increasing pressure to the plantarsurface of the hind paw with a dome-shaped tip placed between the 3rdand 4th metatarsus. Pressure was applied gradually over approximately 10seconds. Measurements were taken from the first observed nocifensivebehavior of vocalization, struggle or withdrawal. A cut-off value of 300g was used to prevent injury to the animal.

Reversal of arthritis pain in the ipsilateral (CFA-injected) paw wascalculated according to the formula:

% reversal=(ipsilateral drug threshold−ipsilateral vehiclethreshold)/(contralateral vehicle threshold−ipsilateral vehiclethreshold)×100.

The experiment was carried out using 7-10 animals per group.

Results:

Oral administration of zoledronic acid significantly improved arthritispain thresholds compared to vehicle. As shown in FIGS. 2A and 2B, orallyadministered zoledronic acid produced a dose-dependent reversal ofarthritis pain. A reversal of 33% was observed in the 54 mg/m² group,and reversal of 54% was observed in the 360 mg/m² group. Under currentFDA guidelines, the reference body surface area of a human adult is 1.62m². Thus, 54 mg/m² in a rat is equivalent to an implied human dose ofabout 87 mg, and 360 mg/m² in a rat is equivalent to an implied humandose of about 583 mg.

Example 3 Treatment of Complex Regional Pain Syndrome with OrallyAdministered Zoledronic Acid

The effect of orally administered zoledronic acid was examined in therat tibia fracture model of complex regional pain syndrome (CRPS). CRPSwas induced in the rats by fracturing the right distal tibias of theanimals and casting the fractured hindpaws for 4 weeks, as described inGuo T Z et al. (Pain. 2004; 108:95-107). This animal model has beenshown to replicate the inciting trauma, natural history, signs,symptoms, and pathologic changes observed in human CRPS patients(Kingery W S et al., Pain. 2003; 104:75-84).

Animals were orally administered either vehicle (control) or zoledronicacid, in a dosage of 18 mg/m²/day (3 mg/kg/day) for 28 days, starting onthe day of fracture and casting. Drug was dissolved in distilled waterand administered by gavage. Animals were fasted for 4 hours before and 2hours after dosing. At the end of the 28-day period, casts were removed,and on the following day, the rats were tested for hindpaw pain, edema,and warmth.

Pain Assessments

Pain was assessed by measuring hyperalgesia, and weight bearing.

To measure hyperalgesia, an up-down von Frey testing paradigm was used.Rats were placed in a clear plastic cylinder (20 cm in diameter) with awire mesh bottom and allowed to acclimate for 15 minutes. The paw wastested with one of a series of eight von Frey hairs ranging in stiffnessfrom 0.41 g to 15.14 g. The von Frey hair was applied against thehindpaw plantar skin at approximately midsole, taking care to avoid thetori pads. The fiber was pushed until it slightly bowed and then it wasjiggled in that position for 6 seconds. Stimuli were presented at aninterval of several seconds. Hindpaw withdrawal from the fiber wasconsidered a positive response. The initial fiber presentation was 2.1 gand the fibers were presented according to the up-down method of Dixonto generate six responses in the immediate vicinity of the 50%threshold. Stimuli were presented at an interval of several seconds.

An incapacitance device (IITC Inc. Life Science, Woodland, Calif., USA)was used to measure hindpaw weight bearing, a postural effect of pain.The rats were manually held in a vertical position over the apparatuswith the hindpaws resting on separate metal scale plates and the entireweight of the rat was supported on the hindpaws. The duration of eachmeasurement was 6 seconds and 10 consecutive measurements were taken at60-second intervals. Eight readings (excluding the highest and lowestones) were averaged to calculate the bilateral hindpaw weight-bearingvalues. Weight bearing data were analyzed as the ratio between right(fracture) and left hindpaw weight bearing values ((2R/(R+L))×100%).

Edema Assessment

A laser sensor technique was used to determine the dorsal-ventralthickness of the hindpaw. Before baseline testing the bilateral hindpawswere tattooed with a 2 to 3 mm spot on the dorsal skin over the midpointof the third metatarsal. For laser measurements each rat was brieflyanesthetized with isoflurane and then held vertically so the hindpawrested on a table top below the laser. The paw was gently held flat onthe table with a small metal rod applied to the top of the ankle joint.Using optical triangulation, a laser with a distance measuring sensorwas used to determine the distance to the table top and to the top ofthe hindpaw at the tattoo site and the difference was used to calculatethe dorsal-ventral paw thickness. The measurement sensor device used inthese experiments (4381 Precicura, Limab, Goteborg, Sweden) has ameasurement range of 200 mm with a 0.01 mm resolution.

Hindpaw Temperature Measurement

The temperature of the hindpaw was measured using a fine wirethermocouple (Omega, Stanford, Conn., USA) applied to the paw skin. Sixsites were tested per hindpaw. The six measurements for each hindpawwere averaged for the mean temperature.

Results

As illustrated in FIG. 3, treatment with orally administered zoledronicacid reversed pain, restored weight bearing, and prevented edema ascompared to vehicle treated animals.

As illustrated in FIG. 4, von Frey pain thresholds for the right(fracture) hindpaw were reduced by 72% versus the contralateral (normal)hindpaw in vehicle treated animals. Zoledronate treatment reversedfracture induced pain by 77% as compared to vehicle treatment.

As illustrated in FIG. 5, reduction in weight bearing, a postural effectof pain, was significantly higher in the vehicle treated group ascompared to the zoledronic acid treated group. Weight bearing on thefracture hindlimb was reduced to 55% of normal in the vehicle treatedgroup. Zoledronate treatment significantly restored hindlimb weightbearing as compared to vehicle treatment (86% of normal).

As illustrated in FIG. 6, the expected increase in hindpaw thickness wasgreater in the vehicle treated group as compared to the zoledronic acidtreated group, reflecting the development of edema. Zoledronatetreatment reduced hindpaw edema by 60% versus vehicle treatment.

Zoledronic acid reduced hindpaw warmth by 5% versus vehicle treatment.

The daily dose in the above experiment was 18 mg/m²/day. Under currentFDA guidelines, the reference body surface area of a human adult is 1.62m². Thus, a daily dose of 18 mg/m² corresponds to a monthly dose ofabout 500-560 mg/m² or a human dose of about 800-900 mg.

Example 6 Solubility of Disodium Salt of Zoledronic Acid

The aqueous solubility of zoledronic acid and disodium zoledronatetetrahydrate was determined. One gram of the test compound was measuredin to a beaker. Demineralized water (pH 5.5) was then added in smallincrements to the test compound, and sonification was applied to themixture. The procedure was continued until complete dissolution wasachieved. Full dissolution was determined to have been reached when aclear solution was present with no visible material. The volume of waterrequired to reach full dissolution was used to calculate a solubilityvalue expressed in grams per 100 mL. The procedure was performed foreach compound.

Results

As shown in FIG. 7, the aqueous solubility of disodium zoledronatetetrahydrate is approximately 50 times that of zoledronic acid. Disodiumzoledronate tetrahydrate has a solubility of 12.5 g/100 mL compared toonly 0.25 g/100 mL for zoledronic acid.

Example 7 Bioavailability of Orally Administered Zoledronic Acid andDisodium Zoledronate

Tablets were manufactured containing either pure zoledronic acid or thedisodium salt of zoledronic acid (disodium zoledronate tetrahydrate).Both types of tablets contained 50 mg of zoledronic acid equivalent pertablet. Identical excipients were used in both types of tablets, withamounts adjusted to account for the difference in molecular weightsbetween the acid and the disodium salt.

Beagle dogs were orally administered tablets containing 150 mgzoledronic acid equivalent either in the form of disodium zoledronate(Group 1) or pure zoledronic acid (Group 2). Each animal was given three50 mg equivalent tablets (150 mg total), which were administeredtogether. The animal's oral cavity was wetted with water before placingthe tablets on the back of the animal's tongue. Animals were fastedbefore and after dosing. Animals were 6 to 9 months of age and weighed 6to 10 kg on the day of dosing. There were three dogs per group.

Serial blood samples were collected from each animal by venipuncture ofthe jugular vein at various points after dosing for measurement ofplasma concentrations of zoledronic acid. Blood samples were collectedinto chilled tubes containing K₂EDTA as the anticoagulant. Samples werethen centrifuged at approximately 3000 rpm at +4° C. for 10 minutes forplasma derivation. Plasma concentrations of zoledronic acid weremeasured using an LC/MS/MS method.

Results

The average plasma concentrations of zoledronic acid for each group ofdogs is summarized in Table 1 and illustrated in FIG. 8. Detectableplasma levels of zoledronic acid were observed for the entire 48 hoursthat they were measured.

TABLE 1 Zoledronic Acid plasma concentrations in beagle dogs Plasma Timeconcentration (hour) (ng/mL) Group 1 (N = 3) Disodium Zoledronate 0 0.00Tablets 0.25 1193.97 (150 mg acid equivalent) 0.5 1852.12 0.75 1776.51 11626.56 2 640.57 4 136.93 6 53.11 8 26.97 12 13.74 24 6.78 48 5.39 Group2 (N = 3) Zoledronic Acid Tablets 0 0.00 (150 mg acid equivalent) 0.25390.92 0.5 846.19 0.75 819.15 1 831.77 2 477.76 4 90.11 6 28.22 8 15.1012 6.13 24 3.18 48 1.84

Disodium zoledronate produced significantly higher plasma levels ofzoledronic acid than pure zoledronic acid, indicating improved oralabsorption with the salt form. Measured using peak plasma concentrations(C_(max)), the disodium salt resulted in a 119% actual and 74%weight-adjusted increase in bioavailability as compared to purezoledronic acid. Measured using area under the plasma concentrationcurve (AUC_(0-∞)), bioavailability was 84% and 46% greater with thedisodium salt than with pure zoledronic acid, on an actual andweight-adjusted basis respectively. The average AUC_(0-∞) for thedisodium salt was 4073 ng·hr/mL and the average AUC_(0-∞) for the diacidwas 2217 ng·hr/mL. The AUC_(0-∞) was found to be dose proportional.Thus, for beagle dogs similar to those tested, about 3 mg to about 4 mgof the disodium salt would be expected to result in an AUC_(0-∞) ofabout 100 ng·hr/mL, and about 7 mg to about 8 mg of the disodium saltwould be expected to result in an AUC_(0-∞) of about 200 ng·hr/mL.

Example 8

Tablets were prepared by blending zoledronic acid, either in the form ofthe free acid or the disodium salt, with identical excipients. Fordosage forms with a greater amount of active, the amount of theexcipients was reduced proportionally to keep the weight of the tabletat about 100 mg. After blending, the ingredients were compressed atvarying pressures, followed by a film coating. The resulting tabletswere then tested for hardness using a Dr. Schleuniger Pharmatron 8MTablet Hardness Tester. The results are shown in Table 2 and FIG. 9.

TABLE 2 Hardness (kPa) Compression Disodium Disodium Force Diacid SaltSalt (psi) 50 mg 50 mg 71 mg 800 4.0 8.7 4.8 1100 6.1 11.2 6.8 1500 7.713.7 7.4 2000 8.7 16.3 10.7 2400 8.7 11.3 3000 11.4 14.1 4400 12.5 14.95500 12.8 18.2 6100 13.0

Example 9

Some embodiments related to joint pain, bone marrow lesions, andosteoarthritis were conceived as a result of analyzing data from aclinical study. Some of the results of this study were reported byLaslett et. al. in Ann Rheum Dis 2012; 71:1322-1328. Some of thedescription and data reported below was not published prior to filingthe present application. Fifty-two (52) patients with clinical kneeosteoarthritis and knee bone marrow lesions (BML) were randomized toreceive either intravenous zoledronic acid (5 mg) or placebo in a doubleblind fashion. All patients had to have at least one bone marrow lesion(BML) in the affected knee on magnetic resonance imaging (MRI). Allpatients had x-ray of the knee for determination of joint spacenarrowing (JSN), which was graded according to the OsteoarthritisResearch Society International (OARSI) atlas. Patients had either nojoint space narrowing (OARSI Grade 0), or greater degrees of joint spacenarrowing (OARSI Grade 1 and Grade 2). Twenty six patients were treatedwith zoledronic acid (8, 6, and 12 with OARSI Grades 0, 1, and 2,respectively). Twenty six patients received placebo (8, 8, and 10 withOARSI Grades 0, 1 and 2, respectively).

Pain intensity was assessed, at baseline and at three months, using a100 mm visual analog scale (VAS), with zero representing no pain and 100representing extreme pain. The change in pain intensity from baseline to3 months was calculated.

With zoledronic acid treatment, pain was reduced significantly ascompared to placebo in patients with no joint space narrowing (OARSIGrade 0), but not in patients with joint space narrowing (OARSI Grades1-2). As shown in Table 3 and FIG. 10, average VAS scores were reducedby 15 mm as compared to placebo in the OARSI Grade 0 group, but only by0.28 as compared to placebo in patients with OARSI Grades 1-2.

In the zoledronic acid group, average VAS scores at 3 months decreasedfrom baseline by approximately 25 mm and 21 mm in patients with OARSIGrades 0 and 1, respectively, but only by 9 mm in the OARSI Grade 2patients (FIG. 11).

TABLE 3 Change in VAS Pain Scores at Three Months by OARSI Grade (mm)OARSI Grade 0 OARSI Grades 1-2 Zoledronic Acid −24.6 −13.2 Placebo −9.6−12.9 Difference from Placebo −15.0 −0.28

With zoledronic acid treatment, pain was reduced significantly ascompared to placebo in patients with baseline VAS pain intensity scoresof 50 mm or greater, but not in patients with baseline VAS scores lessthan 50 mm. As shown in Table 4, average VAS scores were reduced by 9 mmas compared to placebo in the patients with baseline VAS 50 mm, but onlyby 0.6 as compared to placebo in patients with baseline VAS<50 mm.

TABLE 4 Change in VAS Pain Scores at Three Months by Baseline VAS (mm)Baseline VAS ≧50 mm Baseline VAS <50 mm Zoledronic Acid −26.2 −7.3Placebo −17.2 −6.7 Difference from Placebo −9.0 −0.6

As summarized in Table 5 and illustrated in FIG. 12, pain reduction wasgreater in patients with baseline VAS≧50 mm, greater still in patientswith OARSI Grade 0 joint space narrowing, and greatest in patients withboth baseline VAS≧50 mm and OARSI Grade 0 joint space narrowing.

TABLE 5 Pain Reduction Compared to Placebo at Three Months (mm) VASChange All patients −4.8 Baseline VAS ≧50 mm −9.0 OARSI Grade 0 −15.0Baseline VAS ≧50 mm + OARSI Grade 0 −19.4

BMLs were evaluated using proton density-weighted fat saturation MRimages. BMLs were scored using Osiris software (University of Geneva,Geneva, Switzerland). The maximum size was measured in mm² usingsoftware cursors applied to the greatest area of each lesion. The lesionwith the highest score was used if more than one was present at the samesite. Each patient was given a BML score (mm²) at each of the four sites(medial tibial, medial femoral, lateral tibial, and lateral femoralsites) and these were summed to create a total BML score (mm²). Thechange in the total area of BMLs from baseline to 6 months wascalculated.

The size of BMLs was reduced with zoledronic acid treatment. As shown inFIG. 13 and Table 6, average BML area decreased by approximately 190 mm²as compared to placebo in the OARSI Grade 0 group, but only byapproximately 33 mm² as compared to placebo in patients with OARSIGrades 1-2.

TABLE 6 Change in BML Size (mm²) OARSI Grade 0 OARSI Grades 1-2Zoledronic Acid −244 −117 Placebo −55 −84 Difference from Placebo −190−33

Example 10 Methods

A study was performed to evaluate the efficacy of a single intravenousinfusion of 5 mg ZA in comparison with intravenous placebo infusionamong patients with chronic low back pain (LBP) and Modic changes onMRI. This study was a double-blinded, randomized, placebo-controlledclinical trial in patients with low back pain (LBP). Patients wereincluded in the study if they had low back symptoms for at least threemonths, a LBP of at least six (6) on a 10-cm Visual Analog Scale (VAS)or an Oswestry Disability Index (ODI) of at least 30%, and an M1, mixedM1/2 or M2 type change on MRI performed within six months at most priorto enrolment.

Patients were excluded from the study if they had renal impairment withreduced creatinine clearance defined as an estimated glomerularfiltration rate (eGFR) below 40 ml/min, hypocalcemia, knownhypersensitivity to zoledronic acid or other bisphosphonates oringredients of the infusion product, the presence of red flags, nerveroot entrapment or willingness for early retirement. Premenopausal womenof childbearing potential were also excluded. Blood samples were takenprior to the infusion to assess the serum concentration of calcium andcreatinine. The clinical examination included medical history andclinical assessment of lumbar flexibility, tendon signs, and motor andsensory testing.

After confirmation of eligibility patients were randomized to receive asingle intravenous infusion of 5 mg zoledronic acid (n=20) or 100 mlsaline as placebo (n=20) over a 15-minute period. Information on use ofthe concomitant medication and hospital admissions were recorded. Bloodsamples were taken for the assessment of safety, inflammatory mediatorsand markers of bone turnover at baseline, one month and one year.

Clinical assessments were performed 14 days before enrolment (screeningvisit), and follow-up visits at one month and one year after theinfusion. The primary outcome was the change in the intensity of LBP onVAS. Secondary outcomes included leg pain intensity, ODI, health-relatedquality of life assessed with RAND-36, patient-reported sick leaves andlumbar flexibility. These outcome measures were assessed at baseline andat each follow-up. Lumbar flexibility was evaluated using thefingers-to-floor and trunk side bending measures (in cm). The percentageof patients undergoing a 20% relative improvement, the proportion ofpatients reaching a VAS score of 40 or less in the primary outcome, andpatient acceptable symptom state (PASS) were also assessed. Painmedication use was inquired about during the follow-up visits.

Results

Zoledronic acid treatment resulted in a greater improvement in LBPintensity at one month as compared to placebo treatment. Furthermore,the patients receiving zoledronic acid reported NSAID use at one yearsignificantly less often than those in the placebo group. Overall, theimprovements in most of the evaluated parameters were greater in thezoledronic acid group throughout the follow-up period.

The clinical characteristics of study participants at baseline aredisplayed in Table 6. The mean LBP duration was 293 days, initial LBPintensity on VAS 6.7, leg pain on VAS 2.9 and the ODI score was 32%.Altogether 19 patients in the ZA group and 18 in the placebo group had aM1/2 lesion. Modic changes were most commonly (70%) situated at L4/5 orL5/S1. The zoledronic acid and placebo groups were similar as regardsthe demographic and background characteristics of all patients atbaseline (Table 6).

The mean difference (MD) between the treatment groups in the primaryoutcome, intensity of LBP, significantly favored zoledronic acid at onemonth (MD 1.4; 95% CI 0.01 to 2.9) while at one year no significantdifference was observed (MD 0.7; 95% CI—1.0 to 2.4; Table 7). Theproportion of patients with at least 20% improvement in intensity of LBPand PASS both favored the zoledronic acid treatment at one month:zoledronic acid 55% vs. placebo 25% (p=0.105) and zoledronic acid 50%vs. placebo 20% (p=0.096), respectively.

For the patients who were treated with zoledronic acid, the reduction inpain intensity was greater in those with greater baseline pain intensityas shown in Table 9. The mean reduction in pain from baseline was 3.4for patients with baseline pain intensity ≧7, as compared to a reductionof only 0.1 for patients with a baseline pain intensity <6.

Of the secondary outcomes, the improvement in ODI, favored zoledronicacid at 1 month, the adjusted between-group difference being 6.0% (95%CI—0.6 to 13), but not at one year (Table 7). Similarly, side bending(to right and left) favored the zoledronic acid treatment at one monthbut not at one year (Table 7). Changes in total RAND-36, and in thephysical and mental components of RAND-36 are shown in Table 8.

At baseline, there were no differences in self-reported use ofnon-steroidal anti-inflammatory drugs (NSAIDs) between the treatmentgroups, whereas at one year, only 20% of patients in the ZA group usedNSAIDs versus 60% in the placebo group.

TABLE 6 Baseline characteristics of study population according totreatment group Zoledronic Acid Pacebo Characteristics n = 20 n = 20Sex, n (%) men 15 (75) 11 (55) Age, mean (SD) years 49 (9.3) 51 (7.3)Smoking, n (%) regular smokers* 5 (25) 6 (30) BMI, mean (SD) kg/m 26(3.3) 27 (3.2) Workload, n (%) Sedentary work with limited walking 4(20) 4 (22) Fairly light work with considerable walking but no 4 (20) 3(17) lifting or carrying heavy objects Fairly strenuous work withwalking and lifting 8 (40) 6 (33) heaving objects or climbing stairs oruphill Very strenuous work with lifting or carrying 4 (20) 5 (28)heaving objects such as shoveling, digging, or hammering Type of worstMC-lesion**, n Type I 1 1 Type I/II 19 18 Type II 0 1 MC at two or morelevels, n (%) 7 (3.5) 4 (20) Levels of MC, n L2/3 4 0 L3/4 3 5 L4/5 6 5L5/S1 7 10 Duration of LBP, median (IQ range) days 330 (200, 365) 315(270, 365) Intensity of LBP, mean (SD)*** 6.6 (1.4) 6.8 (1.6) Durationof leg pain, median (IQ range) days 50 (0, 100) 36 (0, 160) Intensity ofleg pain, mean (SD)*** 3.0 (3.1) 2.9 (2.3) Oswestry Disability Index, %,Mean (SD) 30 (11) 35 (10) Duration of sick leave during the past year,14 (0, 48) 18 (1, 181) median (IQ range) days RAND-36, mean (SD) 50 (8)50 (7) RAND-36 physical component, mean (SD) 51 (8) 49 (8) RAND-36mental component, mean (SD) 51 (8) 49 (9) BMI = Body Mass Index, MC =Modic Change, LBP = low back pain, SD = standard deviation, IQ =inter-quartile. *Smoking at least one cigarette per day. **If differenttypes of MC at two or more levels, classification is based on theassumed severity of the type, i.e., Type I > mixed Type I/II > Type II.***Assessed using a 10 cm Visual Analogue Scale (VAS).

TABLE 7 Low back symptoms and lumbar flexibility at baseline, one monthand 12 months according to treatment group and between group comparisonsof difference from baseline to one month and 12 months Mean (SD)Unadjusted Adjusted original values Mean (SD) analyses analyses ZAPlacebo change Difference Difference n = 20 n = 20 ZA Placebo (95% CI) P(95% CI) P* Intensity of LBP Baseline 6.6 (1.4) 6.8 (1.6)  1 mo. 4.3(2.3) 5.8 (2.2) −2.2 (2.7) −0.9 (2.1)  1.3 (−0.2 to 2.8) 0.097  1.4(0.01 to 2.9) 0.049 12 mos. 3.8 (2.5) 4.6 (2.9) −2.8 (2.9) −2.2 (2.5) 0.6 (−1.1 to 2.4) 0.474  0.7 (−1.0 to 2.4) 0.387 Intensity of legpain^(a) Baseline 3.0 (3.1) 2.9 (2.3)  1 mo. 2.0 (2.3) 3.0 (2.4) −0.6(2.4)  0.1 (2.6)  0.8 (−0.9 to 2.4) 0.367  0.8 (−0.6 to 2.2) 0.237 12mos. 2.1 (2.8) 2.7 (2.6) −0.9 (3.4) −0.3 (3.0)  0.6 (−1.5 to 2.7) 0.573 0.5 (−1.3 to 2.2) 0.573 Oswestry disability index, % Baseline 30 (11)35 (10)  1 mo. 24 (10) 33 (13) −5.9 (11)  −1.7 (9.7) 4.3 (−2.5 to 11)0.212 6.0 (−0.6 to 13) 0.071 12 mos. 25 (13) 33 (15) −5.0 (15)  −1.9(12)  3.1 (−5.6 to 12) 0.475 5.1 (−3.4 to 14) 0.231 Fingers-to-floor, cmBaseline 23 (19) 19 (18)  1 mo. 17 (17) 19 (17) −5.1 (20)  −0.1 (8.3)5.0 (−4.8 to 15) 0.306 3.6 (−5.0 to 12) 0.403 12 mos. 16 (16) 20 (19)−6.3 (23)   0.9 (11) 7.1 (−4.3 to 18) 0.215 5.3 (−4.5 to 15) 0.277Sidebending to right, cm Baseline 14.1 (4.9)  13.8 (7.2)   1 mo. 15.7(5.9)  13.3 (6.9)   1.5 (4.7) −0.5 (2.2) −2.0 (−4.3 to 0.4)  0.101 −2.0(−4.4 to 0.3)  0.087 12 mos. 15.7 (5.6)  13.8 (6.5)   1.6 (4.8) −0.1(3.5) −1.6 (−4.3 to 1.1)  0.227 −1.7 (−4.2 to 0.8)  0.180 Sidebending toleft, cm Baseline 15.0 (5.4)  13.3 (5.5)   1 mo. 16.1 (5.3)  12.8 (5.9)  1.1 (3.0) −0.5 (2.2) −1.5 (−3.2 to 0.1)  0.072 −1.7 (−3.4 to 0.0) 0.051 12 mos. 16.2 (6.7)  13.7 (5.7)   1.2 (5.3)  0.5 (3.2) −0.7 (−3.5to 2.1)  0.601 −1.0 (−3.8 to 1.8)  0.458 SD = standard deviation, CI =confidence interval, ZA = zoledronic acid, LBP = low back pain. *ANCOVA:Difference between follow-up and baseline, treatment effect adjusted forbaseline value. ^(a)One subject missing at baseline in placebo group andin ZA group, and one subject at 1 month in ZA group.

TABLE 8 Health-related quality of life assessed using RAND-36 atbaseline, one month, and 12 months according to treatment group andbetween group comparisons of difference from baseline to one month and12 months Mean (SD) Unadjusted Adjusted original values Mean (SD)analyses analyses ZA Placebo change Difference Difference n = 20 n = 20ZA Placebo (95% CI) P (95% CI) P* Total RAND-36 Baseline 50 (8) 50 (7) 1 mo. 51 (8) 49 (8) 0.6 (6.4) −0.6 (5.0) 1.2 (−3 to 5) 0.530 1.3 (−3 to5) 0.477 12 mos. 51 (8) 49 (9) 1.0 (8.7) −1.0 (5.9) 2.1 (−3 to 7) 0.3782.2 (−2 to 7) 0.314 Physical component Baseline 52 (8) 48 (8)  1 mo. 52(9) 48 (8) 0.1 (8.6) −0.1 (5.5) 0.3 (−4 to 5) 0.897 1.3 (−3 to 6) 0.55412 mos. 52 (8) 48 (2) 0.3 (10)  −0.3 (6.5) 0.7 (−5 to 6) 0.808 2.1 (−3to 7) 0.405 Mental component Baseline 49 (9) 51 (8)  1 mo. 50 (9) 50 (9)1.0 (6.1) −1.0 (5.6) 2.0 (−2 to 6) 0.286 1.6 (−2 to 5) 0.396 12 mos. 51(9) 49 (9) 1.8 (9.0) −1.8 (6.7) 3.5 (−2 to 9) 0.167 2.7 (−2 to 7) 0.261SD = standard deviation, CI = confidence interval, ZA = zoledronic acid.*ANCOVA: Difference between follow-up and baseline, treatment effectadjusted for baseline value.

TABLE 9 Pain Reduction in Patients Treated Zoledronic Acid (cm) VASChange from Baseline Baseline VAS <6 −0.1 Baseline VAS ≧6 and <7 −2.3Baseline VAS ≧7 −3.4

Example 11

1,3-Bis(2-methoxy-2-oxoethyl)-1H-imidazol-3-ium chloride (9)

Methyl chloroacetate (29.8 mL, 338.6 mmol, 2.0 eq) was added drop-wiseto 1-(trimethylsilyl)-1H-imidazole (8) (25.0 mL, 169.3 mmol). Themixture was heated at 60° C. for 24 hours. The mixture was cooled toroom temperature, washed with Et₂O (3×500 mL) and dried in vacuoyielding 9 (41.97 g, 168.8 mmol, 99.7% yield) as a white solid.

1,3-Bis(carboxymethyl)1H-imidazol-3-ium chloride (10)

To 1,3-bis(2-methoxy-2-oxoethyl)-1H-imidazol-3-ium chloride (9; 41.00 g,164.88 mmol, 1 eq.) was added 37% aqueous HCl (30.03 mL, 362.74 mmol,2.2 eq.). The mixture was stirred under reflux for 0.5 hour. The mixturewas concentrated and the remaining solid was washed with acetone (2×200mL) and Et₂O (3×200 mL), Dried in vacuo to give 10 (31.89 g, 144.55mmol, 87.7% yield) as a white solid.

Compound 1:

Compound 10 is reacted with an equimolar amount of phosphorous acid,followed by an equimolar amount of phosphorous trichloride, and anexcess of water to form Compound 1, which was precipitated out fromethanol, filtered and collected.

Compound 2:

1,3-Bis(carboxymethyl)-1H-imidazol-3-ium chloride (10, 2.00 g, 9 mmol,1.0 eq) and H₃PO₃ (7.37 g, 90 mmol, 10 eq) were dissolved in toluene (10mL) and heated to 70° C. The reaction mixture was stirred at thistemperature for 20 minutes before PCl₃ (16 mL, 180 mmol, 20 eq) wasadded within 30 min. The reaction mixture was then heated to 95° C. andstirred at this temperature for 2 h. Then, aqueous HCl (30 mL, 37% HCland 5 mL H₂O) was added. The reaction mixture was heated to 100° C. andstirred at this temperature for 7 h, then for 2 days at roomtemperature, and filtered. The filtrate was cooled in an ice bath andadded within 45 minutes to absolute EtOH (90 mL). The resulting turbidsolution was stirred for 1 h at room temperature before the solid wasfiltered off. The filter cake (Compound 2) was isolated and analyzed by2D-NMR spectroscopy and mass spectrometry (m/z=477). The filtrate wasconcentrated in vacuo to give a residue. This residue (500 mg) wastreated with aqueous NaOH (150 mg in 3.5 mL H₂O) and EtOH (7 mL). Afterstanding overnight the liquid was decanted and the resulting solid (Nasalt of Compound 2) was obtained and analyzed by NMR and massspectrometry (m/z=477).

The following embodiments are specifically contemplated:

Embodiment 1

A method of relieving inflammatory pain comprising administering an oraldosage form containing zoledronic acid to a mammal in need thereof,wherein the mammal receives a total monthly dose of zoledronic acid thatis about 800 mg/m² or less based upon the body surface area of themammal.

Embodiment 2

The method of embodiment 1, wherein the mammal is a human being thatreceives a total monthly dose of zoledronic acid that is about 30 mg/m²to about 700 mg/m².

Embodiment 3

The method of embodiment 2, wherein the total monthly dose isadministered in 4 or 5 weekly doses.

Embodiment 4

The method of embodiment 2, wherein the total monthly dose isadministered in 28 to 31 daily doses.

Embodiment 5

The method of embodiment 2, wherein the total monthly dose isadministered in 5 to 10 individual doses during the month.

Embodiment 6

The method of embodiment 1, wherein the mammal is a human being thatreceives a total weekly dose of zoledronic acid that is about 10 mg toabout 300 mg.

Embodiment 7

The method of embodiment 6, wherein the total weekly dose is a singledose, administered once a week.

Embodiment 8

The method of embodiment 6, wherein the total weekly dose isadministered in 2 to 7 individual doses during the week.

Embodiment 9

The method of embodiment 1, wherein the mammal is a human being thatreceives a total weekly dose of zoledronic acid that is about 10 mg toabout 150 mg.

Embodiment 10

The method of any preceding embodiment, wherein the mammal experiencessignificant pain relief more than 3 hours after administration of thedosage form.

Embodiment 11

The method of embodiment 10, wherein the mammal experiences significantpain relief during at least a part of a time from about 3 hours to about24 hours after administration of the dosage form.

Embodiment 12

The method of embodiment 10, wherein the mammal experiences significantpain relief during at least a part of a time from about 3 hours to about3 weeks after administration of the dosage form.

Embodiment 13

A method of relieving inflammatory pain comprising administering an oraldosage form containing zoledronic acid to a mammal in need thereof,wherein the oral dosage form contains about 10 mg/m² to about 20 mg/m²of zoledronic acid based upon the body surface area of the mammal.

Embodiment 14

The method of embodiment 13, wherein the oral dosage form contains about15 mg/m² to about 20 mg/m² of zoledronic acid based upon the bodysurface area of the mammal.

Embodiment 15

A method of relieving inflammatory pain comprising orally administeringto a mammal in need thereof, about 300 mg/m² to about 600 mg/m² ofzoledronic acid per month to the mammal, based upon the body surfacearea of the mammal.

Embodiment 16

The method of embodiment 15, comprising orally administering about 450mg/m² to about 600 mg/m² of zoledronic acid per month to the mammal,based upon the body surface area of the mammal.

Embodiment 17

The method of any preceding embodiment, wherein the mammal is notsuffering from bone metastasis.

Embodiment 18

The method of any preceding embodiment, wherein the mammal is notsuffering from cancer.

Embodiment 19

The method of any preceding embodiment, wherein the zoledronic acid isadministered as a salt of a dianion of zoledronic acid.

Embodiment 20

A method of relieving pain associated with an arthritis comprisingadministering an oral dosage form containing zoledronic acid to a humanbeing in need thereof.

Embodiment 21

The method of embodiment 20, wherein the human being receives a totalmonthly dose of zoledronic acid that is about 40 mg to about 2000 mg.

Embodiment 22

The method of embodiment 21, wherein the total monthly dose isadministered in 4 or 5 weekly doses.

Embodiment 23

The method of embodiment 21, wherein the total monthly dose isadministered in 28 to 31 daily doses.

Embodiment 24

The method of embodiment 21, wherein the total monthly dose isadministered in 5 to 10 individual doses during the month.

Embodiment 25

The method of embodiment 20, wherein the human being receives a totalweekly dose of zoledronic acid that is about 100 mg to about 300 mg.

Embodiment 26

The method of embodiment 25, wherein the total weekly dose is a singledose, administered once a week.

Embodiment 27

The method of embodiment 25, wherein the total weekly dose isadministered in 2 to 7 individual doses during the week.

Embodiment 28

The method of embodiment 20, wherein the human being receives a totalweekly dose of zoledronic acid that is about 10 mg to about 100 mg.

Embodiment 29

The method of any of embodiments 20-28, wherein the human beingexperiences significant pain relief more than 3 hours afteradministration of the dosage form.

Embodiment 30

The method of embodiment 29, wherein the human being experiencessignificant pain relief during at least a part of a time from about 3hours to about 24 hours after administration of the dosage form.

Embodiment 31

The method of embodiment 29, wherein the human being experiencessignificant pain relief during at least a part of a time from about 3hours to about 3 weeks after administration of the dosage form.

Embodiment 32

The method of any of embodiments 20-31, wherein the dosage form containsabout 10 mg/m² to about 20 mg/m² of zoledronic acid based upon the bodysurface area of the human being.

Embodiment 33

The method of embodiment 32, wherein the dosage form contains about 15mg/m² to about 20 mg/m² of zoledronic acid based upon the body surfacearea of the human being.

Embodiment 34

The method of any of embodiments 20-33, wherein about 50 mg/m² to about200 mg/m² of zoledronic acid is orally administered per month, basedupon the body surface area of the human being.

Embodiment 35

The method of any of embodiments 20-31, wherein the dosage form containsabout 80 mg/m² to about 150 mg/m² of zoledronic acid based upon the bodysurface area of the human being.

Embodiment 36

The method of embodiment 35, wherein about 300 mg/m² to about 1000 mg/m²of zoledronic acid is orally administered per month, based upon the bodysurface area of the human being.

Embodiment 37

The method of any of embodiments 20-36, wherein the human being is notsuffering from bone metastasis.

Embodiment 38

The method of any of embodiments 20-37, wherein the human being is notsuffering from cancer.

Embodiment 39

The method of any preceding embodiment, wherein the zoledronic acid isin the disodium salt form.

Embodiment 40

An or dosage form comprising zoledronic acid, wherein the oralbioavailability of zoledronic add in the dosage form is about 0.01% toabout 4%.

Embodiment 41

The oral dosage form of embodiment 40, wherein the oral dosage formcontains about 10 mg to about 300 mg of zoledronic acid.

Embodiment 42

The oral dosage form of embodiment 40, wherein the oral dosage formcontains about 10 mg to about 50 mg of zoledronic acid.

Embodiment 43

The or dosage form of any of embodiments 40-42, wherein the oralbioavailability of zoledronic acid in the dosage form is about 0.1% toabout 2%.

Embodiment 44

A pharmaceutical product comprising more than one unit of an oral dosageform of embodiment 40.

Embodiment 45

The pharmaceutical product of embodiment 44, wherein each unit of theoral dosage form contains about 1 mg to about 50 mg of zoledronic acid.

Embodiment 46

The pharmaceutical product of embodiment 45, comprising 28, 29, 30, or31 units of the oral dosage form, for a total of about 28 mg to about1600 mg of zoledronic acid to be administered in about 1 month.

Embodiment 47

The pharmaceutical product of embodiment 45, comprising 85 to 95 unitsof the oral dosage form, for a total of about 85 mg to about 4800 mg ofzoledronic acid to be administered in about 3 months.

Embodiment 48

The pharmaceutical product of embodiment 45, comprising 170 to 200 unitsof the oral dosage form, for a total of about 170 mg to about 10,000 mgof zoledronic acid to be administered in about 6 months.

Embodiment 49

The pharmaceutical product of embodiment 45, comprising 350 to 380 unitsof the oral dosage form, for a total of about 350 mg to about 19,000 mgof zoledronic acid to be administered in about 1 year.

Embodiment 50

The pharmaceutical product of embodiment 44, wherein each unit of theoral dosage form contains about 10 mg to about 300 mg.

Embodiment 51

The pharmaceutical product of embodiment 50, comprising 4 or 5 units ofthe oral dosage form, for a total of about 40 mg to about 1500 mg ofzoledronic acid to be administered within a period of about 1 month.

Embodiment 52

The pharmaceutical product of embodiment 50, comprising 8 or 9 units ofthe oral dosage form, for a total of about 80 mg to about 2700 mg ofzoledronic acid to be administered in about 2 months.

Embodiment 53

The pharmaceutical product of embodiment 50, comprising 12, 13 or 14units of the oral dosage form, for a total of about 120 mg to about 4200mg of zoledronic acid to be administered in about 3 months.

Embodiment 54

The pharmaceutical product of embodiment 50, comprising 22 to 30 unitsof the oral dosage form, for a total of about 220 mg to about 9000 mg ofzoledronic acid to be administered in about 6 months.

Embodiment 55

The pharmaceutical product of embodiment 50, comprising 45 to 60 unitsof the oral dosage form, for a total of about 450 mg to about 18000 mgof zoledronic acid to be administered in about 1 year.

Embodiment 56

The pharmaceutical product of embodiment 44, comprising 1 to 10 units ofthe oral dosage form, wherein the product contains about 200 mg to about2000 mg of zoledronic acid.

Embodiment 57

The oral dosage form of any preceding embodiment, wherein the zoledronicacid is in the form of a sodium salt.

Embodiment 58

The oral dosage form of any preceding embodiment, wherein the zoledronicacid is in a form that has an aqueous solubility greater than 1% (w/v).

Embodiment 59

The oral dosage form of any preceding embodiment, wherein the zoledronicacid is in a form that has an aqueous solubility of about 5% (w/v) toabout 50% (w/v).

Embodiment 60

An oral dosage form comprising zoledronic acid and an excipient, whereinthe zoledronic acid is in a form that has an aqueous solubility greaterthan 1% (w/v).

Embodiment 61

The oral dosage form of embodiment 60, wherein the zoledronic acid is ina form that has an aqueous solubility of about 5% (w/v) to about 50%(w/v).

Embodiment 62

A method of treating complex regional pain syndrome comprisingadministering an oral dosage form containing zoledronic acid to a mammalin need thereof.

Embodiment 63

The method of embodiment 62, wherein the mammal is a human being thatreceives an amount of zoledronic acid that is about 30 mg/m² to about700 mg/m² in a period of one month or less.

Embodiment 64

The method of embodiment 63, wherein 4 or 5 weekly doses areadministered in a period of one month or less.

Embodiment 65

The method of embodiment 63, wherein 28 to 31 daily doses areadministered in a period of one month or less.

Embodiment 66

The method of embodiment 63, wherein 5 to 10 individual doses areadministered during a period of one month or less.

Embodiment 67

The method of embodiment 63, wherein about 30 mg/m² to about 700 mg/m²of zoledronic acid is administered during only one month.

Embodiment 68

The method of embodiment 63, wherein about 30 mg/m² to about 700 mg/m²of zoledronic acid is administered in a period of one month or less for2 or more consecutive months.

Embodiment 69

The method of embodiment 62, wherein the mammal receives about 10 mg/m²to about 30 mg/m² of zoledronic acid daily.

Embodiment 70

The method of embodiment 62, wherein the mammal is a human being thatreceives a total weekly dose of zoledronic acid that is about 10 mg toabout 300 mg.

Embodiment 71

The method of embodiment 70, wherein the total weekly dose is a singledose, administered once a week.

Embodiment 72

The method of embodiment 70, wherein the total weekly dose isadministered in 2 to 7 individual doses during the week.

Embodiment 73

The method of any of embodiments 62-72, wherein the complex regionalpain syndrome is complex regional pain syndrome type I.

Embodiment 74

The method of any of embodiments 62-72, wherein the complex regionalpain syndrome is complex regional pain syndrome type II.

Embodiment 75

The method of any preceding embodiment, wherein the zoledronic acid isin a salt form.

Embodiment 76

The method of any of embodiments 62-75, wherein the dosage form containsabout 10 mg/m² to about 20 mg/m² of zoledronic acid based upon the bodysurface area of the mammal.

Embodiment 77

The method of embodiment 76, wherein the dosage form contains about 15mg/m² to about 20 mg/m² of zoledronic acid based upon the body surfacearea of the mammal.

Embodiment 78

A method of treating complex regional pain syndrome, comprisingadministering pamidronic acid to a human being in need thereof.

Embodiment 79

A method of treating complex regional pain syndrome, comprisingadministering neridronic acid to a human being in need thereof.

Embodiment 80

A method of treating complex regional pain syndrome, comprisingadministering olpadronic acid to a human being in need thereof.

Embodiment 81

A method of treating complex regional pain syndrome, comprisingadministering alendronic acid to a human being in need thereof.

Embodiment 82

A method of treating complex regional pain syndrome, comprisingadministering incadronic acid to a human being in need thereof.

Embodiment 83

A method of treating complex regional pain syndrome, comprisingadministering ibandronic acid to a human being in need thereof.

Embodiment 84

A method of treating complex regional pain syndrome, comprisingadministering risedronic acid to a human being in need thereof.

Embodiment 85

A method of treating pain, comprising administering pamidronic acid to ahuman being in need thereof.

Embodiment 86

A method of treating pain, comprising administering neridronic acid to ahuman being in need thereof.

Embodiment 87

A method of treating pain, comprising administering olpadronic acid to ahuman being in need thereof.

Embodiment 88

A method of treating pain, comprising administering alendronic acid to ahuman being in need thereof.

Embodiment 89

A method of treating pain, comprising administering incadronic acid to ahuman being in need thereof.

Embodiment 90

A method of treating pain, comprising administering ibandronic acid to ahuman being in need thereof.

Embodiment 91

A method of treating pain, comprising administering risedronic acid to ahuman being in need thereof.

Embodiment 92

A method of treating arthritis pain, comprising administering pamidronicacid to a human being in need thereof.

Embodiment 93

A method of treating arthritis pain, comprising administering neridronicacid to a human being in need thereof.

Embodiment 94

A method of treating arthritis pain, comprising administering olpadronicacid to a human being in need thereof.

Embodiment 95

A method of treating arthritis pain, comprising administering alendronicacid to a human being in need thereof.

Embodiment 96

A method of treating arthritis pain, comprising administering incadronicacid to a human being in need thereof.

Embodiment 97

A method of treating arthritis pain, comprising administering ibandronicacid to a human being in need thereof.

Embodiment 98

A method of treating arthritis pain, comprising administering risedronicacid to a human being in need thereof.

Embodiment 99

A method of treating inflammatory pain, comprising administeringpamidronic acid to a human being in need thereof.

Embodiment 100

A method of treating inflammatory pain, comprising administeringneridronic acid to a human being in need thereof.

Embodiment 101

A method of treating inflammatory pain, comprising administeringolpadronic acid to a human being in need thereof.

Embodiment 102

A method of treating inflammatory pain, comprising administeringalendronic acid to a human being in need thereof.

Embodiment 103

A method of treating inflammatory pain, comprising administeringincadronic acid to a human being in need thereof.

Embodiment 104

A method of treating inflammatory pain, comprising administeringibandronic acid to a human being in need thereof.

Embodiment 105

A method of treating inflammatory pain, comprising administeringrisedronic acid to a human being in need thereof.

Embodiment 106

A method of treating complex regional pain syndrome, comprisingadministering etidronic acid to a human being in need thereof.

Embodiment 107

A method of treating pain, comprising administering etidronic acid to ahuman being in need thereof.

Embodiment 108

A method of treating arthritis pain, comprising administering etidronicacid to a human being in need thereof.

Embodiment 109

A method of treating inflammatory pain, comprising administeringetidronic acid to a human being in need thereof.

Embodiment 110

A method of treating complex regional pain syndrome, comprisingadministering clodronic acid to a human being in need thereof.

Embodiment 111

A method of treating pain, comprising administering clodronic acid to ahuman being in need thereof.

Embodiment 112

A method of treating arthritis pain, comprising administering clodronicacid to a human being in need thereof.

Embodiment 113

A method of treating inflammatory pain, comprising administeringclodronic acid to a human being in need thereof.

Embodiment 114

A method of treating complex regional pain syndrome, comprisingadministering tiludronic acid to a human being in need thereof.

Embodiment 115

A method of treating pain, comprising administering tiludronic acid to ahuman being in need thereof.

Embodiment 116

A method of treating arthritis pain, comprising administering tiludronicacid to a human being in need thereof.

Embodiment 117

A method of treating inflammatory pain, comprising administeringtiludronic acid to a human being in need thereof.

Embodiment 118

The method of any of embodiments 78-117, wherein the active compound isorally administered.

Embodiment 119

The method of any of embodiments 78-117, wherein the active compound isparenterally administered.

Embodiment 120

A method of enhancing the oral bioavailability of zoledronic acidcomprising orally administering a dosage form containing zoledronic acidin the disodium salt form.

Embodiment 121

The method of embodiment 120, wherein the zoledronic acid in thedisodium salt form provides an enhancement to bioavailability, ascompared to zoledronic acid in the diacid form, which adds to anyenhancement to bioavailability provided by any bioavailability-enhancingagents in the dosage form.

Embodiment 122

The method of embodiment 120, wherein the dosage form is substantiallyfree of bioavailability-enhancing agents.

Embodiment 123

The method of embodiment 120, wherein the zoledronic acid in thedisodium salt form is administered to a mammal in an amount thatprovides an area under the plasma concentration curve of zoledronic acidof about 4 ng·h/mL to about 2000 ng·h/mL to the mammal each time thezoledronic acid in the disodium salt is administered.

Embodiment 124

The method of embodiment 123, wherein the zoledronic acid in thedisodium salt form is administered at an interval of about 3 to about 4weeks in an amount that provides an area under the plasma concentrationcurve of zoledronic acid of about 100 ng·h/mL to about 2000 ng·h/mL tothe mammal each time the zoledronic acid in the disodium salt form isadministered.

Embodiment 125

The method of embodiment 123, wherein the zoledronic acid in thedisodium salt form is administered weekly, or 3 to 5 times in a month,in an amount that provides an area under the plasma concentration curveof zoledronic acid of about 20 ng·h/mL to about 700 ng·h/mL to themammal each time the zoledronic acid in the disodium salt form isadministered.

Embodiment 126

The method of embodiment 123, wherein the zoledronic acid in thedisodium salt form is administered daily in an amount that provides anarea under the plasma concentration curve of zoledronic acid of about 4ng·h/mL to about 100 ng·h/mL to the mammal each time the zoledronic acidin the disodium salt form is administered.

Embodiment 127

The method of embodiment 120, wherein the dosage form is a solid.

Embodiment 128

The method of embodiment 120, 121, 122, 123, 124, 125, 126, or 127,wherein the bioavailability of zoledronic acid is improved by at leastabout 20% as compared to administration of zoledronic acid in the diacidform.

Embodiment 129

The method of embodiment 120, 121, 122, 123, 124, 125, 126, 127, or 128,further comprising administering, on a molar basis, less of thezoledronic acid in the disodium salt form than would be administered ofzoledronic acid in the diacid form in order to achieve the same plasmalevels of zoledronic acid.

Embodiment 130

The method of embodiment 129, wherein at least about 10 mole % less ofthe disodium salt form is administered as compared the amount ofzoledronic acid in the diacid form that would be administered in orderto achieve the same plasma levels of zoledronic acid.

Embodiment 131

The method of embodiment 129, wherein the disodium salt form isadministered in an amount, on a molar basis, that has a value of about0.8n_(d) to about 1.2n_(d), wherein:

n _(d)=(b _(a) /b _(d))(n _(a))

wherein b_(a) is the bioavailability of the diacid form, b_(d) is thebioavailability of the disodium salt form, and n_(a) is the number ofmoles of zoledronic acid in the diacid form that would be administeredin order to achieve the same plasma levels of zoledronic acid.

Embodiment 132

The method of embodiment 131, wherein the disodium salt is administeredin an amount that has a value of about n_(d).

Embodiment 133

The method of any of embodiments 120-132, wherein the zoledronic acid isused to treat an inflammatory condition.

Embodiment 134

The method of embodiment 133, wherein the zoledronic acid is used totreat arthritis.

Embodiment 135

The method of embodiment 133, wherein the zoledronic acid is used totreat complex regional pain syndrome.

Embodiment 136

The method of any of embodiments 1-39, 62-77, and 120-135, wherein:

a first oral dosage form is administered; and

a second oral dosage form is administered;

wherein, with respect to the first oral dosage form, the second oraldosage form is administered at 10×T_(max) or greater, wherein T_(max) isthe time of maximum plasma concentration for the first oral dosage form.

Embodiment 137

A dosage form comprising zoledronic acid in the disodium salt form,wherein the bioavailability, in a mammal, of zoledronic acid in thedisodium salt form is greater than the bioavailability of zoledronicacid in the diacid form would be in the same dosage form.

Embodiment 138

A dosage form comprising zoledronic acid in the disodium salt form,wherein the dosage form contains an amount of zoledronic acid in thedisodium salt form that provides an area under the plasma concentrationcurve of zoledronic acid of about 4 ng·h/mL to about 2000 ng·h/mL to ahuman being to which the dosage form is administered.

Embodiment 139

The dosage form of embodiment 138, wherein the dosage form contains anamount of zoledronic acid in the disodium salt form that provides anarea under the plasma concentration curve of zoledronic acid of about100 ng·h/mL to about 2000 ng·h/mL to a human being to which the dosageform is administered.

Embodiment 140

The dosage form of embodiment 138, wherein the dosage form contains anamount of zoledronic acid in the disodium salt form that provides anarea under the plasma concentration curve of zoledronic acid of about 20ng·h/mL to about 700 ng·h/mL to a human being to which the dosage formis administered.

Embodiment 141

The dosage form of embodiment 138, wherein the dosage form contains anamount of zoledronic acid in the disodium salt form that provides anarea under the plasma concentration curve of zoledronic acid of about 4ng·h/mL to about 100 ng·h/mL to a human being to which the dosage formis administered.

Embodiment 142

A dosage form comprising zoledronic acid in the disodium salt form,

wherein the disodium salt form is present in a lower molar amount thanwould be present if the zoledronic acid were in the diacid form; and

wherein the zoledronic acid in the disodium salt form has an improvedbioavailability as compared to the zoledronic acid in the diacid form tothe extent that the lower molar amount of the disodium salt in thedosage form does not reduce the amount of zoledronic acid delivered tothe plasma of a mammal.

Embodiment 143

The dosage form of embodiment 137, 138, 139, 140, 141, or 142, whereinthe dosage form is a solid.

Embodiment 144

The dosage form of embodiment 142 or 143, wherein the bioavailability ofzoledronic acid in the disodium salt form is improved by at least about10% as compared to an otherwise identical dosage form containingzoledronic acid in the diacid form.

Embodiment 145

The dosage form of embodiment 142, 143, or 144, containing at leastabout 20 mole % less of the disodium salt form as compared to the amountof the zoledronic acid in the diacid form that would be present if thezoledronic acid were in the diacid form.

Embodiment 146

The dosage form of embodiment 142, wherein the disodium salt form ispresent in an amount, on a molar basis, that has a value of about 0.9ndto about 1.1nd, wherein:

n _(d)=(b _(a) /b _(d))(n _(a))

wherein b_(a) is the bioavailability of the diacid form, b_(d) is thebioavailability of the disodium salt form, and n_(a) is the number ofmoles of the diacid form that would be present if the zoledronic acidwere in the diacid form.

Embodiment 147

The dosage form of embodiment 146, wherein the disodium salt isadministered in an amount that has a value of about n_(d).

Embodiment 148

The method of any of embodiments 1-39, 62-77, and 120-136, wherein:

only a single oral dosage form is administered; or

a first oral dosage form is administered, and a second oral dosage formis administered after the first oral dosage form, wherein the secondoral dosage form is administered before the maximum pain relievingeffect of the first oral dosage form is achieved, or the second oraldosage form is administered before an observable pain relieving effectis achieved.

Embodiment 149

The method of embodiment 148, wherein the second oral dosage form isadministered before an observable pain relieving effect is achieved.

Embodiment 150

The method of any of embodiments 1-39, 62-77, and 120-132, wherein afirst dosage form is administered, followed by administration of asecond dosage form, wherein the second dosage form is administered afterthe maximum pain relieving effect of the first oral dosage form isachieved, and the second oral dosage form is administered while a painrelieving effect from the first oral dosage form is observable.

Embodiment 151

The method of embodiment 148, 149, or 150, wherein the second oraldosage form is administered about 24 hours to about 28 days after thefirst oral dosage form is administered.

Embodiment 152

The method of any of embodiments 20-39, wherein the human being is about30 years old to about 75 years old.

Embodiment 153

The method of any of embodiments 20-39, wherein the human being is about1 year old to about 16 years old.

Embodiment 154

The method of any of embodiments 20-39, wherein the human being is about80 years old to about 95 years old.

Embodiment 155

The method of any of embodiments 20-39, wherein the human being hassuffered from the arthritis for at least 2 months.

Embodiment 156

The method of any of embodiments 20-39, wherein the arthritis affects, aknee, an elbow, a wrist, a shoulder, or a hip.

Embodiment 157

The method of any of embodiments 1-44, 62-133, and 144-156, wherein themammal or human being to which the zoledronic acid is administered doesnot eat food or drink beverage for at least 1 hour before the zoledronicacid is administered.

Embodiment 158

The method of embodiment 157, wherein the mammal or human being to whichthe zoledronic acid is administered does not eat food or drink beveragefor at least 2 hours before the zoledronic acid is administered.

Embodiment 159

The method of embodiment 158, wherein the mammal or human being to whichthe zoledronic acid is administered does not eat food or drink beveragefor at least 4 hours before the zoledronic acid is administered.

Embodiment 160

The method of embodiment 159, wherein the mammal or human being to whichthe zoledronic acid is administered does not eat food or drink beveragefor at least 6 hours before the zoledronic acid is administered.

Embodiment 161

The method of any of embodiments 157-160, wherein the mammal or humanbeing to which the zoledronic acid is administered does not eat food ordrink beverage for at least 30 minutes after the zoledronic acid isadministered.

Embodiment 162

The method of embodiment 161, wherein the mammal or human being to whichthe zoledronic acid is administered does not eat food or drink beveragefor at least 1 hour after the zoledronic acid is administered.

Embodiment 163

The method of embodiment 161, where in the mammal or human being towhich the zoledronic acid is administered does not eat food or drinkbeverage for at least 2 hours after the zoledronic acid is administered.

Embodiment 164

The method, dosage form, or product, of any preceding embodiment,wherein the zoledronic acid in the oral dosage form has a 24 hoursustained plasma level factor of about 1 or higher.

Embodiment 165

The method, dosage form, or product, of any preceding embodiment,wherein the zoledronic acid in the oral dosage form has a 24 hoursustained plasma level factor that is higher than that of intravenouslyadministered zoledronic acid.

Embodiment 166

The method, dosage form, or product, of any preceding embodiment,wherein the oral dosage form is a solid that has a hardness of about 5kPa to about 20 kPa.

Embodiment 167

A method of treating bone marrow lesions comprising: selecting a patienthaving a bone marrow lesion and OARSI grade 0 of joint space narrowing,and administering an inhibitor of osteoclast activity to the patient forthe treatment of the bone marrow lesion.

Embodiment 168

The method of embodiment 167, wherein the inhibitor of osteoclastactivity is administered at least twice.

Embodiment 169

The method of embodiment 167, wherein the inhibitor of osteoclastactivity is administered about every three months, or more frequently.

Embodiment 170

The method of embodiment 167, wherein the inhibitor of osteoclastactivity comprises a nitrogen-containing bisphosphonate.

Embodiment 171

The method of any one of embodiments 167-170, wherein the inhibitor ofosteoclast activity is or comprises zoledronic acid.

Embodiment 172

The method of any one of embodiments 167-170, wherein the inhibitor ofosteoclast activity is or comprises pamidronic acid.

Embodiment 173

The method of any one of embodiments 167-170, wherein the inhibitor ofosteoclast activity is or comprises neridronic acid.

Embodiment 174

The method of any one of embodiments 167-170, wherein the inhibitor ofosteoclast activity is or comprises olpadronic acid.

Embodiment 175

The method of any one of embodiments 167-170, wherein the inhibitor ofosteoclast activity is or comprises alendronic acid.

Embodiment 176

The method of any one of embodiments 167-170, wherein the inhibitor ofosteoclast activity is or comprises incadronic acid.

Embodiment 177

The method of any one of embodiments 167-170, wherein the inhibitor ofosteoclast activity is or comprises ibandronic acid.

Embodiment 178

The method of any one of embodiments 167-170, wherein the inhibitor ofosteoclast activity is or comprises risedronic acid.

Embodiment 179

The method of any one of embodiments 167-178, wherein the inhibitor ofosteoclast activity is administered orally.

Embodiment 180

The method of any one of embodiments 167-178, wherein the inhibitor ofosteoclast activity is administered intravenously.

Embodiment 181

The method of any one of embodiments 167-180, wherein the patientexperiences a reduction in bone marrow lesion size that is at leastabout 100% greater than a reduction in bone marrow lesion size achievedwith a placebo.

Embodiment 182

The method of any one of embodiments 167-180, wherein the patientexperiences a reduction in bone marrow lesion size that is at leastabout 150% greater than a reduction in bone marrow lesion size achievedwith a placebo.

Embodiment 183

The method of any one of embodiments 167-182, wherein the inhibitor ofosteoclast activity is administered at least twice over a period of atleast four weeks.

Embodiment 184

The method of any one of embodiments 167-183, wherein the inhibitor ofosteoclast activity is administered once weekly for a period of sixweeks.

Embodiment 185

The method of any one of embodiments 167-184, wherein the inhibitor ofosteoclast activity comprises zoledronic acid, and the weekly dose isbetween about 25 mg and about 75 mg.

Embodiment 186

A method of treating knee pain comprising: selecting a patient havingknee pain and OARSI grade 0 of joint space narrowing, and administeringan inhibitor of osteoclast activity to the patient for the treatment ofthe knee pain.

Embodiment 187

The method of embodiment 186, wherein the inhibitor of osteoclastactivity is administered at least twice.

Embodiment 188

The method of any one of embodiments 186-187, wherein the inhibitor ofosteoclast activity is administered about every three months, or morefrequently.

Embodiment 189

The method of any one of embodiments 186-188, wherein the inhibitor ofosteoclast activity comprises a nitrogen-containing bisphosphonate.

Embodiment 190

The method of any one of embodiments 186-189, wherein the patientexperiences pain relief three months after administration of theinhibitor of osteoclast activity.

Embodiment 191

The method of any one of embodiments 186-190, wherein the inhibitor ofosteoclast activity is or comprises zoledronic acid.

Embodiment 192

The method of any one of embodiments 186-190, wherein the inhibitor ofosteoclast activity is or comprises pamidronic acid.

Embodiment 193

The method of any one of embodiments 186-190, wherein the inhibitor ofosteoclast activity is or comprises neridronic acid.

Embodiment 194

The method of any one of embodiments 186-190, wherein the inhibitor ofosteoclast activity is or comprises olpadronic acid.

Embodiment 195

The method of any one of embodiments 186-190, wherein the inhibitor ofosteoclast activity is or comprises alendronic acid.

Embodiment 196

The method of any one of embodiments 186-190, wherein the inhibitor ofosteoclast activity is or comprises incadronic acid.

Embodiment 197

The method of any one of embodiments 186-190, wherein the inhibitor ofosteoclast activity is or comprises ibandronic acid.

Embodiment 198

The method of any one of embodiments 186-190, wherein the inhibitor ofosteoclast activity is or comprises risedronic acid.

Embodiment 199

The method of any one of embodiments 186-198, wherein the patientexperiences a reduction in pain intensity—when using a 100 mm visualanalog scale—of at least about 20.

Embodiment 200

A method of treating a bone marrow lesion of the knee comprising:selecting a patient having a bone marrow lesion of the knee and OARSIGrade 0 or Kellgren and Lawrence Grade 0 or Grade 1 of joint spacenarrowing, and administering an inhibitor of osteoclast activity to thepatient for the treatment of the bone marrow lesion.

Embodiment 201

The method of embodiment 200, wherein the inhibitor of osteoclastactivity is administered at least twice.

Embodiment 202

The method of embodiment 201, wherein the inhibitor of osteoclastactivity is administered about every three months, or more frequently.

Embodiment 203

The method of embodiment 200, wherein the inhibitor of osteoclastactivity comprises a nitrogen-containing bisphosphonate.

Embodiment 204

The method of embodiment 203, wherein the inhibitor of osteoclastactivity is zoledronic acid.

Embodiment 205

The method of embodiment 203, wherein the inhibitor of osteoclastactivity is pamidronic acid.

Embodiment 206

The method of embodiment 203, wherein the inhibitor of osteoclastactivity is neridronic acid.

Embodiment 207

The method of embodiment 203, wherein the inhibitor of osteoclastactivity is olpadronic acid.

Embodiment 208

The method of embodiment 203, wherein the inhibitor of osteoclastactivity is minodronic acid.

Embodiment 209

The method of embodiment 203, wherein the inhibitor of osteoclastactivity is incadronic acid.

Embodiment 210

The method of embodiment 203, wherein the inhibitor of osteoclastactivity is ibandronic acid.

Embodiment 211

The method of embodiment 203, wherein the inhibitor of osteoclastactivity is risedronic acid.

Embodiment 212

The method of embodiment 203, wherein the inhibitor of osteoclastactivity is alendronic acid.

Embodiment 213

The method of embodiment 200, wherein the inhibitor of osteoclastactivity is administered orally.

Embodiment 214

The method of embodiment 200, wherein the inhibitor of osteoclastactivity is administered intravenously.

Embodiment 215

The method of embodiment 200, wherein the patient experiences areduction in bone marrow lesion size that is at least about 15% withinabout 6 months after the inhibitor of osteoclast activity isadministered to the patient.

Embodiment 216

The method of embodiment 200, wherein the patient experiences areduction in bone marrow lesion size that is at least about 25% withinabout 6 months after the inhibitor of osteoclast activity isadministered to the patient.

Embodiment 217

The method of embodiment 201, wherein the inhibitor of osteoclastactivity is administered at least twice over a period of at least fourweeks.

Embodiment 218

The method of embodiment 201, wherein the inhibitor of osteoclastactivity is administered once weekly for a period of six weeks.

Embodiment 219

The method of embodiment 218, wherein the inhibitor of osteoclastactivity comprises zoledronic acid, and the weekly dose is between about25 mg and about 75 mg.

Embodiment 220

A method of treating knee pain comprising:

-   -   a. selecting a patient having knee pain, and:        -   i. OARSI Grade 0 or Kellgren and Lawrence Grade 0 or Grade 1            of joint space narrowing, or        -   ii. pain intensity of 5 or greater measured using the 0-10            NRS or 5 cm or greater using the 10 cm VAS; and    -   b. administering an inhibitor of osteoclast activity to the        patient.

Embodiment 221

The method of embodiment 220, comprising selecting a patient havingOARSI Grade 0 or Kellgren and Lawrence Grade 0 or Grade 1 of joint spacenarrowing.

Embodiment 222

The method of embodiment 220 or 221, comprising selecting a patienthaving pain intensity of 5 or greater measured using the 0-10 NRS or 5cm or greater using the 10 cm VAS.

Embodiment 223

The method of embodiment 220, wherein the inhibitor of osteoclastactivity is administered at least twice.

Embodiment 224

The method of embodiment 223, wherein the inhibitor of osteoclastactivity is administered about every three months, or more frequently.

Embodiment 225

The method of embodiment 220, wherein the inhibitor of osteoclastactivity comprises a nitrogen-containing bisphosphonate.

Embodiment 226

The method of embodiment 220, wherein the patient experiences painrelief within about three months after the inhibitor of osteoclastactivity is administered to the patient.

Embodiment 227

The method of embodiment 226, wherein the patient experiences painrelief at least 24 hours after the inhibitor of osteoclast activity isadministered to the patient.

Embodiment 228

The method of embodiment 220, wherein the inhibitor of osteoclastactivity is zoledronic acid.

Embodiment 229

The method of embodiment 220, wherein the inhibitor of osteoclastactivity is minodronic acid.

Embodiment 230

The method of embodiment 220, wherein the inhibitor of osteoclastactivity is neridronic acid.

Embodiment 231

The method of embodiment 220, wherein the inhibitor of osteoclastactivity is olpadronic acid.

Embodiment 232

The method of embodiment 220, wherein the inhibitor of osteoclastactivity is alendronic acid.

Embodiment 233

The method of embodiment 220, wherein the inhibitor of osteoclastactivity is incadronic acid.

Embodiment 234

The method of embodiment 220, wherein the inhibitor of osteoclastactivity is ibandronic acid.

Embodiment 235

The method of embodiment 220, wherein the inhibitor of osteoclastactivity is risedronic acid.

Embodiment 236

The method of embodiment 220, wherein the patient experiences areduction in pain intensity—when using a 100 mm visual analog scale—ofat least about 5.

Embodiment 237

The method of embodiment 220, wherein the inhibitor of osteoclastactivity is administered at least twice over a period of at least fourweeks.

Embodiment 238

The method of embodiment 220, wherein the inhibitor of osteoclastactivity is administered once weekly for a period of six weeks.

Embodiment 239

The method of embodiment 238, wherein the inhibitor of osteoclastactivity comprises zoledronic acid, and the weekly dose is between about25 mg and about 75 mg.

Embodiment 240

A method of treating moderate to severe knee pain comprisingadministering an inhibitor of osteoclast activity to a person sufferingfrom moderate to severe knee pain.

Embodiment 241

The method of embodiment 240, wherein the person suffering from moderateto severe knee pain has a normal joint space in the knee.

Embodiment 242

The method of embodiment 240, wherein the inhibitor of osteoclastactivity is administered at least twice.

Embodiment 243

The method of embodiment 240, wherein the inhibitor of osteoclastactivity is administered about every three months, or more frequently.

Embodiment 244

The method of embodiment 240, wherein the inhibitor of osteoclastactivity comprises a nitrogen-containing bisphosphonate.

Embodiment 245

The method of embodiment 240, wherein the patient experiences painrelief within about three months after the inhibitor of osteoclastactivity is administered to the patient.

Embodiment 246

The method of embodiment 245, wherein the patient experiences painrelief at least 24 hours after the inhibitor of osteoclast activity isadministered to the patient.

Embodiment 247

The method of embodiment 240, wherein the inhibitor of osteoclastactivity is zoledronic acid.

Embodiment 248

The method of embodiment 240, wherein the inhibitor of osteoclastactivity is minodronic acid.

Embodiment 249

The method of embodiment 240, wherein the inhibitor of osteoclastactivity is neridronic acid.

Embodiment 250

The method of embodiment 240, wherein the inhibitor of osteoclastactivity is olpadronic acid.

Embodiment 251

The method of embodiment 240, wherein the inhibitor of osteoclastactivity is alendronic acid.

Embodiment 252

The method of embodiment 240, wherein the inhibitor of osteoclastactivity is incadronic acid.

Embodiment 253

The method of embodiment 240, wherein the inhibitor of osteoclastactivity is ibandronic acid.

Embodiment 254

The method of embodiment 240, wherein the inhibitor of osteoclastactivity is risedronic acid.

Embodiment 255

The method of embodiment 240, wherein the patient experiences areduction in pain intensity—when using a 100 mm visual analog scale—ofat least about 5.

Embodiment 256

The method of embodiment 240, wherein the inhibitor of osteoclastactivity is administered at least twice over a period of at least fourweeks.

Embodiment 257

The method of embodiment 240, wherein the inhibitor of osteoclastactivity is administered once weekly for a period of six weeks.

Embodiment 258

The method of embodiment 257, wherein the inhibitor of osteoclastactivity comprises zoledronic acid, and the weekly dose is between about25 mg and about 75 mg.

Embodiment 259

A method of safely delivering zoledronic acid to the blood of a mammalthrough repeated oral administration comprising:

orally administering about 0.4 mg/kg to about 4 mg/kg of zoledronic acidto the mammal no more frequently than once a day and more frequentlythan once a week; or orally administering about 0.4 mg/kg to about 10mg/kg to the mammal once a week, or less frequently.

Embodiment 260

The method of any preceding embodiment, such as embodiment 259, whereinabout 0.5 mg/kg to about 2 mg/kg is orally administered to the mammaldaily.

Embodiment 261

The method of any preceding embodiment, such as embodiment 260, whereinabout 0.6 mg/kg to about 0.9 mg/kg is orally administered to the mammaldaily.

Embodiment 262

The method of any preceding embodiment, such as embodiment 259, whereinabout 0.5 mg/kg to about 2 mg/kg is orally administered to the mammalweekly.

Embodiment 263

The method of any preceding embodiment, such as embodiment 263, whereinabout 0.6 mg/kg to about 0.9 mg/kg is orally administered to the mammalweekly.

Embodiment 264

The method of any preceding embodiment, such as embodiment 259, 260,261, 262, or 263, wherein zoledronic acid is orally administered about 3to about 10 times.

Embodiment 265

The method of any preceding embodiment, such as embodiment 259, 260,261, 262, 263, or 264, wherein zoledronic acid is orally administered ina dosage form comprising more than about 10% zoledronic acid by weight.

Embodiment 266

The method of any preceding embodiment, such as embodiment 259, 260,261, 262, 263, 264, or 265, wherein zoledronic acid is administered in amanner and amount that results in the mammal having an AUC₀₋₂₄ ofzoledronic acid that is about 50 ng·h/mL to about 500 ng·h/mL with eachadministration of zoledronic acid.

Embodiment 267

The method of any preceding embodiment, such as embodiment 266, whereinzoledronic acid is administered in a manner and amount that results inthe mammal having an AUC₀₋₂₄ of zoledronic acid that is about 100ng·h/mL to about 500 ng·h/mL with each administration of zoledronicacid.

Embodiment 268

A method of preparing an oral dosage form that is safe for repeatedadministration to a mammal comprising combining zoledronic acid with anexcipient that is pharmaceutically acceptable to the mammal, wherein theamount of zoledronic acid that is combined with the excipient is suchthat zoledronic acid is present in the oral dosage form in an amountthat is 0.4 mg/kg to about 10 mg/kg based upon the weight of the mammal.

Embodiment 269

The method of any preceding embodiment, such as embodiment 268, whereinthe amount of zoledronic acid that is combined with the excipient issuch that the oral dosage form comprises more than about 10% zoledronicacid by weight.

Embodiment 270

The method of any preceding embodiment, such as embodiment 268 or 269,wherein the amount of zoledronic acid that is combined with theexcipient is such that zoledronic acid is present in the oral dosageform in an amount that is 0.4 mg/kg to about 3 mg/kg based upon theweight of the mammal.

Embodiment 271

The method of any preceding embodiment, such as embodiment 270, whereinthe amount of zoledronic acid that is combined with the excipient issuch that zoledronic acid is present in the oral dosage form in anamount that is 0.4 mg/kg to about 1.5 mg/kg based upon the weight of themammal.

Embodiment 272

The method of any preceding embodiment, such as embodiment 270, whereinthe amount of zoledronic acid that is combined with the excipient issuch that zoledronic acid is present in the oral dosage form in anamount that is 0.6 mg/kg to about 0.9 mg/kg based upon the weight of themammal.

Embodiment 273

The method of any preceding embodiment, such as embodiment 268, 269,270, 271, or 272, wherein the oral dosage form is safe for once dailyadministration of the oral dosage form for about 3 to about 10 days.

Embodiment 274

The method of any preceding embodiment, such as embodiment 268, 269,270, 271, or 272, wherein the oral dosage form is safe for once weeklyadministration of the oral dosage form for about 3 to about 10 weeks.

Embodiment 275

A method of safely delivering zoledronic acid to the blood of a mammalthrough repeated oral administration comprising:

-   -   orally administering about 0.05 mg/kg to about 4 mg/kg of        zoledronic acid to the mammal no more frequently than once a day        and more frequently than once a week; or    -   orally administering about 0.1 mg/kg to about 10 mg/kg to the        mammal once a week, or less frequently

wherein zoledronic acid is orally administered at least 5 times.

Embodiment 276

The method of any preceding embodiment, such as embodiment 275, whereinzoledronic acid is orally administered about 5 to about 10 times.

Embodiment 277

The method of any preceding embodiment, such as embodiment 275 or 276,wherein zoledronic acid is orally administered in a dosage formcomprising more than about 10% zoledronic acid by weight.

Embodiment 278

The method of any preceding embodiment, such as embodiment 259, 260,261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274,275, 276, or 277, wherein the mammal is a human being.

Embodiment 279

The method of any preceding embodiment, such as embodiment 259, 260,261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274,275, 276, 277, or 278, wherein about 50 mg to about 350 mg of oralzoledronic acid is administered to the mammal per month.

Embodiment 280

An oral dosage form prepared by the method of any preceding embodiment,such as embodiment 259, 260, 261, 262, 263, 264, 265, 266, 267, 268,269, 270, 271, 272, 273, 274, 275, 276, 277, 278, or 279.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodin all instances as indicating both the exact values as shown and asbeing modified by the term “about.” Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary depending upon thedesired properties sought to be obtained. At the very least, and not asan attempt to limit the application of the doctrine of equivalents tothe scope of the claims, each numerical parameter should at least beconstrued in light of the number of reported significant digits and byapplying ordinary rounding techniques.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of any claim. Nolanguage in the specification should be construed as indicating anynon-claimed element essential to the practice of the invention.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the invention. Of course, variationson these described embodiments will become apparent to those of ordinaryskill in the art upon reading the foregoing description. The inventorexpects skilled artisans to employ such variations as appropriate, andthe inventors intend for the invention to be practiced otherwise thanspecifically described herein. Accordingly, the claims include allmodifications and equivalents of the subject matter recited in theclaims as permitted by applicable law. Moreover, any combination of theabove-described elements in all possible variations thereof iscontemplated unless otherwise indicated herein or otherwise clearlycontradicted by context.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the claims. Other modificationsthat may be employed are within the scope of the claims. Thus, by way ofexample, but not of limitation, alternative embodiments may be utilizedin accordance with the teachings herein. Accordingly, the claims are notlimited to embodiments precisely as shown and described.

What is claimed is:
 1. A method of safely and effectively deliveringzoledronic acid to the blood of a human being through repeated oraladministration comprising: mixing zoledronic acid with a diluent,binder, an excipient, a disintegrating agent, a flavoring agent, or alubricant to form a pharmaceutical composition containing at least 20%zoledronic acid by weight; wherein the pharmaceutical composition is inthe form of a pill, tablet, or capsule, and containing about 0.15millimoles to about 1.1 millimoles of zoledronic acid in the acid or asalt form; and wherein the pill, tablet, or capsule is orallyadministered to a human being at least twice a month and no morefrequently than once a day.
 2. The method of claim 1, wherein, about0.15 millimoles to about 0.22 millimoles of zoledronic acid is orallyadministered weekly.
 3. The method of claim 2, wherein the pill, tablet,or capsule containing zoledronic acid is orally administered for about 6weeks.
 4. The method of claim 1, wherein the pill, tablet, or capsulecomprises more than about 30% zoledronic acid by weight.
 5. The methodof claim 2, wherein the pill, tablet, or capsule comprises more thanabout 30% zoledronic acid by weight.
 6. The method of claim 3, whereinthe pill, tablet, or capsule comprises more than about 30% zoledronicacid by weight.
 7. The method of claim 1, wherein the zoledronic acid isorally administered in a manner that results in a 24 hour sustainedplasma level factor that is at least 1.5 times that of 4 mg ofzoledronic acid administered intravenously.
 8. The method of claim 2,wherein the zoledronic acid is orally administered in a manner thatresults in a 24 hour sustained plasma level factor that is at least 1.5times that of 4 mg of zoledronic acid administered intravenously.
 9. Themethod of claim 3, wherein the zoledronic acid is orally administered ina manner that results in a 24 hour sustained plasma level factor that isat least 1.5 times that of 4 mg of zoledronic acid administeredintravenously.
 10. The method of claim 1, wherein the zoledronic acid isorally administered in a manner that results in a 24 hour sustainedplasma level factor that is at least twice that of 4 mg of zoledronicacid administered intravenously.
 11. The method of claim 2, wherein thezoledronic acid is orally administered in a manner that results in a 24hour sustained plasma level factor that is at least twice that of 4 mgof zoledronic acid administered intravenously.
 12. The method of claim3, wherein the zoledronic acid is orally administered in a manner thatresults in a 24 hour sustained plasma level factor that is at leasttwice that of 4 mg of zoledronic acid administered intravenously. 13.The method of claim 1, wherein the zoledronic acid is orallyadministered in a manner that results in a 48 hour sustained plasmalevel factor that is at least twice that of 4 mg of zoledronic acidadministered intravenously.
 14. The method of claim 2, wherein thezoledronic acid is orally administered in a manner that results in a 48hour sustained plasma level factor that is at least twice that of 4 mgof zoledronic acid administered intravenously.
 15. The method of claim3, wherein the zoledronic acid is orally administered in a manner thatresults in a 48 hour sustained plasma level factor that is at leasttwice that of 4 mg of zoledronic acid administered intravenously. 16.The method of claim 1, wherein zoledronic acid is orally administered ina manner that results in a bioavailability that is 1.3% to 4%.
 17. Themethod of claim 2, wherein zoledronic acid is orally administered in amanner that results in a bioavailability that is 1.3% to 4%.
 18. Themethod of claim 3, wherein zoledronic acid is orally administered in amanner that results in a bioavailability that is 1.3% to 4%.
 19. Themethod of claim 1, wherein zoledronic acid is orally administered in amanner that results in a bioavailability that is 1.8% to 3%.
 20. Themethod of claim 2, wherein zoledronic acid is orally administered in amanner that results in a bioavailability that is 1.8% to 3%.
 21. Themethod of claim 3, wherein zoledronic acid is orally administered in amanner that results in a bioavailability that is 1.8% to 3%.
 22. Themethod of claim 1, wherein the zoledronic acid is orally administered ina dosage form that, other than a counter-ion to zoledronic acid,contains no agents which enhance the bioavailability of zoledronic acid.23. The method of claim 2, wherein the zoledronic acid is orallyadministered in a dosage form that, other than a counter-ion tozoledronic acid, contains no agents which enhance the bioavailability ofzoledronic acid.
 24. The method of claim 3, wherein the zoledronic acidis orally administered in a dosage form that, other than a counter-ionto zoledronic acid, contains no agents which enhance the bioavailabilityof zoledronic acid.
 25. The method of claim 1, wherein the human beingis not suffering from a blood cancer.
 26. The method of claim 2, whereinthe human being is not suffering from a blood cancer.
 27. The method ofclaim 3, wherein the human being is not suffering from a blood cancer.28. The method of claim 1, wherein the zoledronic acid is orallyadministered in a solid dosage form having a binder.
 29. The method ofclaim 2, wherein the zoledronic acid is orally administered in a soliddosage form having a binder.
 30. The method of claim 3, wherein thezoledronic acid is orally administered in a solid dosage form having abinder.